Biomedical subjects

M P Look

Publications and source records attributed to M P Look.

At least 19 recordsLinked to original sources

PubMed2003

Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease.

Besides a variety of other proteases, polymorphonuclear leukocyte elastase (PMN-E) is also suggested to play a role in the processes of tumour cell invasion and metastasis. Yet, there is only limited data available on the relation between the tumour level of PMN-E and prognosis in patients with primary breast cancer, and no published information exists on its relation with the efficacy of response to systemic therapy in patients with advanced breast cancer. In the present study, we have measured with enzyme-linked immunosorbent assay the levels of total PMN-E in cytosolic extracts of 463 primary breast tumours, and have correlated their levels with the rate and duration of response on first-line tamoxifen therapy (387 patients) or chemotherapy (76 patients) in patients with locally advanced and/or distant metastatic breast cancer. Furthermore, the probabilities of progression-free survival and postrelapse survival were studied in relation to the tumour levels of PMN-E. Our results show that in logistic regression analysis for response to tamoxifen treatment in patients with advanced disease, high PMN-E tumour levels were associated with a poor rate of response compared with those with low PMN-E levels (odds ratio: OR, 0.40; 95% CI, 0.22-0.73; P=0.003). After correction for the contribution of the traditional predictive factors in multivariate analysis, the tumour PMN-E status was an independent predictor of response (P=0.01). Furthermore, a high tumour PMN-E level was related with a poor progression-free survival (P<0.001) and postrelapse survival (P=0.002) in a time-dependent analysis. In contrast, the tumour level of PMN-E was not significantly related with the efficacy of response to first-line chemotherapy in patients with advanced breast cancer. Our present results suggest that PMN-E is an independent predictive marker for the efficacy of tamoxifen treatment in patients with advanced breast cancer.

Adult↗

PubMed2002

Higher expression of human kallikrein 10 in breast cancer tissue predicts tamoxifen resistance.

The human tissue kallikreins are secreted serine proteases, encoded by a group of homologous genes clustered in tandem on chromosome 19q13.3-4. Human kallikrein 6 and human kallikrein 10 are two new members of this family. Recently, we developed highly sensitive and specific immunofluorometric assays for human kallikrein 6 and human kallikrein 10, which allow for their quantification in tissue extracts and biological fluids. Both human kallikrein 6 and human kallikrein 10 are found to be down-regulated in breast cancer cell lines, suggesting that they may be involved in breast cancer pathogenesis and progression. In this study, we investigated the potential value of human kallikrein 6 and human kallikrein 10 as prognostic and predictive factors in breast cancer. We quantified human kallikrein 6 and human kallikrein 10 protein levels in 749 breast tumour cytosolic extracts and correlated this data with various clinicopathological variables and patient outcomes. Human kallikrein 6 and human kallikrein 10 are positively correlated with each other. Higher human kallikrein 6 and human kallikrein 10 protein levels are associated with younger age, pre-menopausal, status and tumours which are negative for oestrogen and progesterone receptors. No correlation was found between human kallikrein 6 and human kallikrein 10 levels and tumour size, grade, and nodal status. Survival analysis showed that neither human kallikrein 6 nor human kallikrein 10 are related to the rate of relapse-free and overall survival. In the analysis with respect to response to tamoxifen therapy, although human kallikrein 6 levels were not associated with tamoxifen responsiveness, higher levels of human kallikrein 10 were significantly associated with a poor response rate. This association remained significant in the multivariate analysis. Furthermore, higher human kallikrein 10 levels were significantly related with a short progression-free and post-relapse overall survival after start of tamoxifen treatment for advanced disease. Taken together, our results suggest that although human kallikrein 6 and human kallikrein 10 are not prognostic markers for breast cancer, human kallikrein 10 is an independent predictive marker for response of tamoxifen therapy.

Adult↗

PubMed2001

Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2.

Traditional clinicopathological features do not predict which patients will develop chemotherapy resistance. The TP53 gene is frequently altered in ovarian cancer but its prognostic implications are controversial. Little is known on the impact of TP53-downstream genes on prognosis. Using molecular and immunohistochemical analyses we examined TP53 and its downstream genes p21, BAX and BCL-2 in ovarian tumour tissues and have evaluated the results in relation to clinico-pathological parameters, clinical outcome and response to platinum-based chemotherapy. Associations of tested factors and patient and tumour characteristics were studied by Spearman rank correlation and Pearsons chi2 test. The Cox proportional hazard model was used for univariate and multivariate analysis. The associations of tested factors with response was tested using logistic regression analysis. TP53 mutation, p21 and BCL-2 expression were not associated with increased rates of progression and death. Expression of TP53 was associated with a shorter overall survival only (relative hazard rate [RHR] 2.01, P = 0.03). Interestingly, when combining TP53 mutation and expression data, this resulted in an increased association with overall survival (P = 0.008). BAX expression was found to be associated with both progression-free (RHR 0.44, P = 0.05) and overall survival (RHR 0.42, P = 0.03). Those patients who simultaneously expressed BAX and BCL-2 had a longer progression-free and overall survival compared to patients whose tumours did not express BCL-2 (P = 0.05 and 0.015 respectively). No relations were observed between tested factors and response to platinum-based chemotherapy. We conclude that BAX expression may represent a prognostic indicator for patients with ovarian cancer and that the combined evaluation of BAX and BCL-2 may provide additional prognostic significance.

Adult↗

PubMed2001

High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer.

Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be associated with a poor prognosis in primary breast cancer and in several other cancer types. In the present study, we have measured with ELISA the levels of VEGF in cytosolic extracts of 845 primary breast tumors of patients who developed a recurrence during follow-up. All of the patients received tamoxifen (n = 618) or cyclophosphamide, methotrexate, 5-fluorouracil (CMF) or 5-fluorouracil, Adriamycin, cyclophosphamide (FAC) chemotherapy (n = 227) as first-line systemic therapy after diagnosis of advanced disease. VEGF levels were not related to age or menopausal status but were negatively related to the cytosolic levels of estrogen receptor and progesterone receptor (P < 0.0001). In patients who relapsed within 1 year after primary surgery, tumor VEGF levels were higher than in patients who showed a longer disease-free interval (P = 0.0005). In patients with a first relapse in the viscera, VEGF levels were higher compared with those that relapsed to the bone or soft tissue (P = 0.0004). In univariate analysis for response to first-line tamoxifen therapy, patients with high or intermediate levels showed a poor rate of response, compared with patients with low tumor-VEGF levels (P = 0.0001). Similarly, in multivariate analysis for response to tamoxifen treatment, corrected for age, site of relapse, disease-free interval, and estrogen receptor and progesterone receptor status, VEGF status was an independent predictive factor (P = 0.009). In concordance, higher levels of VEGF were associated with a short progression-free survival and postrelapse overall survival (both, P < 0.0001). On first-line chemotherapy, the rate of response decreased with higher tumor levels of VEGF, both in univariate (P = 0.003) and in multivariate analysis (P = 0.004). Furthermore, higher VEGF levels were associated with a short progression-free survival (P = 0.003) and postrelapse overall survival (P = 0.001). In conclusion, the tumor VEGF level is an important independent marker that predicts a poor efficacy of both tamoxifen and chemotherapy in advanced breast cancer. Knowledge of the tumor level of VEGF might be helpful in selecting individual patients who may benefit from treatments with antiangiogenic agents combined with conventionally used drugs.

Adult↗

PubMed2001

Prognostic impact of urokinase-type plasminogen activator receptor (uPAR) in cytosols and pellet extracts derived from primary breast tumours.

Using a previously developed enzyme-linked immunosorbent assay (ELISA), the levels of the receptor for urokinase-type plasminogen activator (uPAR) were determined in cytosols and corresponding membrane pellets derived from 878 primary breast tumours. The levels of uPAR in the pellet extracts were more than 3-fold higher than those measured in the cytosols (P< 0.001). Moreover, the uPAR levels in the two types of extracts were weakly, though significantly, correlated with each other (rS= 0.20, P< 0.001). In Cox univariate analysis, high cytosolic levels of uPAR were significantly associated with reduced overall survival (OS) and relapse-free survival (RFS). The levels of uPAR in pellet extracts appeared not to be related with patient survival. In multivariate analysis, elevated levels of uPAR measured in cytosols and pellet extracts were found to be independent predictors of poor OS, not RFS. The prediction of poor prognosis on the basis of high uPAR levels emphasizes its important role in plasmin-mediated degradation of extracellular matrix proteins during cancer invasion and metastasis.

Adult↗

PubMed2001

Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy.

Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy.

Adult↗

PubMed2001

Clinical relevance of biologic factors in male breast cancer.

There is ample information on the clinical role of biologic factors in female breast cancer: urokinase-type plasminogen activator (uPA), its receptor uPAR, its inhibitors PAI-1 and PAI-2, cathepsin D and pS2-protein. However such reports are missing or very rare for male breast cancer. We determined the cytosolic levels of oestrogen receptor (ER), progesterone receptor (PgR), cathepsin D, pS2-protein, uPA, uPAR, PAI-1 and PAI-2 of the primary tumour tissues from 40 male breast cancer patients. The tumour levels were compared with those of 180 matched females and 4114 historic females with breast cancer. In male breast tumours the level of PgR was higher, those of uPA, PAI-1, PAI-2 and cathepsin D lower. The tumour level of ER in men was similar to those in the matched and postmenopausal women, but much higher than those in the historic women. Male breast cancer seems to be biologically different from female breast cancer. Correlation of the eight cell biologic factors with disease outcome showed that PAI-1 (p = 0.03) was the only independent predictive factor for poor prognosis in male breast cancer.

Adult↗

PubMed2001

Decrease of elevated N,N-dimethylglycine and N-methylglycine in human immunodeficiency virus infection during short-term highly active antiretroviral therapy.

This study investigates fasting serum levels of methionine and related metabolites, vitamin B6, and folate during highly active antiretroviral therapy in therapy-naive human immunodeficiency virus (HIV)-1-infected outpatients. The research design consisted of before and during therapy measurements with a median treatment period of 100 days (range, 50 to 188) in frozen samples. The subjects included 17 consecutive HIV-1-infected outpatients (15 men and 2 women; 25 to 65-years-old). Controls were 42 healthy individuals (28 men and 14 women; 24- to 82-years-old) without serologic evidence of HIV and/or hepatitis C infection and normal clinical chemistry. Subjects received treatment with the reverse transcriptase inhibitors, azidothymidine (AZT) or stavudine (D4T) plus lamivudine (3TC) and either the protease inhibitors, indinavir (IND), nelfinavir (NELF), ritonavir (RITV), or saquinavir (SAQ) at the standard dosage. Serum concentrations of methionine, total homocysteine (tHcy), cystathionine (CYSTA), N,N-dimethylglycine (DMG), N-methylglycine (MG), methylmalonic acid (MMA), and total cysteine, as well as vitamin B6, folate, and soluble tumor necrosis factor receptor p75 were taken at baseline and during highly active antiretroviral therapy. Baseline, serum tHcy, MMA, CYSTA, vitamin B6 concentrations were not significantly different from healthy controls. There was, however, a trend towards lower folate serum concentrations at baseline in HIV-infected patients as compared with healthy controls (P =.06). There were no significant correlations between tHcy and vitamin B6, folate, or MMA. Elevated baseline levels of DMG and MG decreased significantly during antiretroviral therapy (P =.0019 and.04, respectively), whereas no significant changes in serum concentrations of CYSTA, MMA, or methionine were detected. tHcy increased in 12 of 17 patients (P =.09). HIV-infected patients displayed significant alterations (elevated DMG and MG serum concentrations) in metabolite levels of the betaine pathway in methionine metabolism, which might be positively influenced by newly initiated antiretroviral combination therapy.

Adult↗

PubMed2000

Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease.

The chronic immune activation state in HIV disease leads to increased activity of the rate-limiting tryptophan-kynurenine pathway enzyme indoleamine 2,3-dioxygenase (2,3-IDO), thereby increasing the formation of neurotoxic tryptophan metabolites such as kynurenine and quinolinic acid. We investigated whether highly active antiretroviral therapy (HAART) (median duration, 100 days; range, 50-188 days) lowers serum levels of these metabolites in HIV-infected individuals and if so, whether this was paralleled by changes in a surrogate marker for immune activation, i.e., soluble tumor necrosis factor receptor p75 (sTNFR p75) concentrations. Baseline quinolinic acid (848 nM, 95% CI 567-1130 vs. 303 nM, 95% CI 267.1-339.5) and kynurenine (4.1 microM, 95% CI 3.3-4.9 vs. 2.7 microM, 95% CI 2.4-2.9) concentrations as well as the mean kynurenine-to-tryptophan ratio (108.2, 95% CI 76.1-140.4 vs. 51.4, 95% CI 47.6-55.3) in 17 HIV-1-infected outpatients (7 with AIDS) were significantly higher than those in 55 healthy age-matched controls (p < 0.01), respectively. Serum quinolinic acid concentrations in 14 of 17 patients decreased (mean, -44.4%) during HAART in comparison with baseline (471.2 nM, 95% CI 288-654.3; p = 0. 022). Thirteen of these 14 patients also had decreases in sTNFR p75 concentrations. Overall, the mean sTNFR p75 concentration decreased by 36.3% (13.5 ng/ml, 95% CI 9.3-17.8 vs. 8.6 ng/ml, 95% CI 5.9-11. 4; p = 0.01, n = 17). Reduction in viral load through HAART and subsequent mitigation of the pathological immune activation state in HIV disease may have reduced 2,3-IDO over activation. This eventually led to a decrease in quinolinic acid formation. The parallel reduction of the immune activation marker sTNFR p75 supports this hypothesis.

Adult↗

PubMed2000

Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer.

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.

Aged↗

PubMed2000

The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients.

The antigen levels of components of the urokinase-type plasminogen activator (uPA) system of plasminogen activation are correlated with prognosis in several types of cancers, including breast cancer. In the present study involving 2780 patients with primary invasive breast cancer, we have evaluated the prognostic importance of the four major components of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1 and PAI-2]. The antigen levels were determined by ELISA in cytosols prepared from primary breast tumors. The levels of the four factors significantly correlated with each other; the Spearman rank correlation coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to 0.59 (between uPA and PAI-1). The median duration of follow-up of patients still alive was 88 months. In the multivariate analyses for relapse-free survival (RFS) and overall survival (OS), we defined a basic model including age, menopausal status, tumor size and grade, lymph node status, adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1, and PAI-2 were considered as categorical variables, each with two cut points that were established by isotonic regression analysis. Compared with tumors with low levels, those with intermediate and high levels showed a relative hazard rate (RHR) and 95% confidence interval (95% CI) of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and 2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS in all patients. Compared with tumors with high PAI-2 levels, those with intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30 (1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were obtained in the multivariate analysis for OS in all patients. Furthermore, uPA and PAI-1 were independent predictive factors of a poor RFS and OS in node-negative and node-positive patients. PAI-2 also added to the multivariate models for RFS in node-negative and node-positive patients, and in the analysis for OS in node-negative patients. uPAR did not further contribute to any of the multivariate models. A prognostic score was calculated based on the estimates from the final multivariate model for RFS. Using this score, the difference between the highest and lowest 10% risk groups was 66% in the analysis for RFS at 10 years and 61% in the analysis for OS. Moreover, separate prognostic scores were calculated for node-negative and node-positive patients. In the 10% highest risk groups, the proportion of disease-free patients was only 27 +/- 6% and 9 +/- 3% at 10 years for node-negative and node-positive patients, respectively. These proportions were 86 +/- 4% and 61 +/- 6% for the corresponding 10% lowest risk groups of relapse. We conclude that several components of the uPA system are potential predictors of RFS and OS in patients with primary invasive breast cancer. Knowledge of these factors could be helpful to assess the individual risk of patients, to select various types of adjuvant treatment and to identify patients who may benefit from targeted therapies that are currently being developed.

Adult↗

PubMed2000

Bcar1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment.

BACKGROUND: The product of the Bcar1/p130Cas (breast cancer resistance/p130Crk-associated substrate) gene causes resistance to antiestrogen drugs in human breast cancer cells in vitro. To investigate its role in clinical breast cancer, we determined the levels of Bcar1/p130Cas protein in a large series of primary breast carcinomas. METHODS: We measured Bcar1/p130Cas protein in cytosol extracts from 937 primary breast carcinomas by western blot analysis. The levels of Bcar1/p130Cas protein were tested for associations and trends against clinicopathologic and patient characteristics, the lengths of relapse-free survival and overall survival (n = 775), and the efficacy of first-line treatment with tamoxifen for recurrent or metastatic disease (n = 268). RESULTS: Bcar1/p130Cas levels in primary tumors were associated with age/menopausal status and the levels of estrogen receptor and progesterone receptor. In univariate survival analysis, higher Bcar1/p130Cas levels were associated with poor relapse-free survival and overall survival (both two-sided P =.04; log-rank test for trend). In multivariate analysis, a high level of Bcar1/p130Cas was independently associated with poor relapse-free survival and overall survival. The response to tamoxifen therapy in patients with recurrent disease was reduced in patients with primary tumors that expressed high levels of Bcar1/p130Cas. In multivariate analysis for response, Bcar1/p130Cas was independent of classical predictive factors, such as estrogen receptor status, age/menopausal status, disease-free interval, and dominant site of relapse. CONCLUSION: Patients with primary breast tumors expressing a high level of Bcar1/p130Cas protein appear to experience more rapid disease recurrence and have a greater risk of (intrinsic) resistance to tamoxifen therapy. Thus, measurement of Bcar1/p130Cas may provide useful prognostic information for patients with primary or metastatic breast cancer.

Adult↗

PubMed2000

The urokinase-type plasminogen activator system in resected non-small-cell lung cancer. Rotterdam Oncology Thoracic Study Group.

BACKGROUND: Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitors (PAI-1 and PAI-2), all play important roles in tumour invasion and metastasis. The tumour levels of the components of the urokinase-type plasminogen activator system (uPA-system) may help to identify individuals with a poor prognosis in postoperative non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: The levels of uPA, uPAR PAI-1 and PAI-2 were measured by enzyme-linked immunosorbent assay (ELISA) in triton-extracts, prepared from 88 NSCLC tissues (stage I-IIIa) and 74 normal lung tissues from the same patients. RESULTS: The expression levels of uPA, uPAR, PAI-1 and PAI-2 were significantly higher in tumour tissues as compared to their normal equivalents (all, P < 0.0001). Significant relations were found between gender and uPA (P = 0.04) or uPAR (P < 0.001), and between PAI-2 and pathological stage (P = 0.03). For none of the studied factors of the uPA-system a significant relation with survival was found, neither in all patients, nor in the subgroups of patients with squamous-cell lung carcinoma or adenocarcinoma. CONCLUSIONS: The expression levels of the components of the uPA-system were higher in NSCLC tissue as compared to normal lung tissue, but there were no significant relationships between their levels and survival.

Carcinoma, Non-Small-Cell Lung↗

PubMed2000

Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase?

BACKGROUND: It has been suggested that the major metabolic block in the methionine catabolic pathway in cirrhotics exists at the level of the enzyme S-adenosylmethionine synthetase because in previous studies using conventional amino-acid analyzers, no intermediates of transmethylation/transsulfuration were found to accumulate in plasma downstream of S-adenosylmethionine synthesis. We therefore measured serum concentration intermediates of methionine transmethylation/transsulfuration using an improved gas chromatography/mass spectrometry technique. METHODS: Serum concentrations of methionine, homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, 2-methylcitric acid and alpha-aminobutyric acid were determined by gas chromatography/mass spectrometry in 108 consecutive patients with liver cirrhosis at Child stages A (mild cirrhosis, n = 27) and B/C (severe cirrhosis, n = 81), 18 outpatients with non-cirrhotic liver disease, and 55 healthy individuals. RESULTS: Serum levels of methionine, N,N-dimethylglycine, N-methylglycine, cystathionine, and homocysteine were significantly higher in patients at Child stages B/C compared with those of healthy controls (P < 0.01), and they were also significantly higher than in patients with non-cirrhotic liver disease (P < 0.01 and P < 0.05 for homocysteine, respectively). They also correlated with the Child-Pugh score (P < 0.01). Homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, and 2-methylcitric acid correlated with serum creatinine. The mean cystathionine concentration was significantly higher in patients with creatinine > or = 1.4 mg/dl than in patients with normal creatinine values (P < 0.01). However, the differences between cirrhotics and healthy controls were still significant after correcting for creatinine. CONCLUSIONS: Our data provides indirect evidence for two hitherto unrecognized alterations of methionine metabolism in cirrhotics, i.e. impairment of the transsulfuration of homocysteine at the level of cystathionine degradation and a shift in remethylation of homocysteine towards the betaine-homocysteine-methyltransferase reaction.

Adolescent↗

PubMed2000

Elevated soluble tumour necrosis factor receptor serum concentrations and short-term mortality in liver cirrhosis without acute infections.

BACKGROUND: Serum concentrations of the soluble 75-kDa tumour necrosis factor receptor (sTNF-R 75) are elevated in patients with severe liver disease and may be linked to mortality as well as to prognostic markers related to clinical outcome and metabolic functions in patients with liver cirrhosis. PATIENTS AND METHODS: We prospectively studied the relation of sTNF-R 75 to Child-Pugh score points and serum markers of bile acid (total serum bile acids and 7alpha-hydroxycholesterol), lignocaine (lignocaine metabolite (MEGX) liver function test results) and albumin metabolism (albumin and prealbumin) in 10 healthy individuals and 30 patients with cirrhosis, all free of acute infections. In patients with cirrhosis mortality was recorded for 15 months. RESULTS: Soluble TNF-R 75 concentrations correlated with Child-Pugh score points (r = 0.440, p = 0.015), MEGX test results (r(S) = -0.604, p < 0.001) and prealbumin (r(S) = -0. 527, p < 0.001) in cirrhosis. Nonsurviving patients had almost threefold higher median sTNF-R 75 concentrations (29 ng/ml) than survivors (11 ng/ml) (p = 0.003). Soluble TNF-R 75 serum concentrations with an optimal cut off > 14 ng/ml were significantly more accurate in predicting patient mortality than Child-Pugh score points in a receiver-operator characteristic curve analysis. CONCLUSION: Soluble TNF-R 75 serum concentrations appear to be a promising new risk factor for mortality in patients with cirrhosis without acute infections.

Adult↗

PubMed1999

Prognostic value of CD44 variant expression in primary breast cancer.

CD44 is a family of cell surface transmembrane glycoproteins members which differ in the extracellular part by sequences derived by alternative splicing of 10 variant exons (v1-v10). CD44 proteins containing such variant sequences have been implicated in tumor metastasis formation. Here, we have evaluated the expression of CD44 variants by immuno-histochemistry in primary breast cancer samples of 237 node-negative and 230 node-positive patients. For the analysis of samples derived from node-negative patients, the exon-specific antibodies used were DIII, vff7 and vff18 (v6), vff17 (v7/v8), fw11.24 (v9) and vff16 (v10). With the different antibodies which recognize v6 epitopes, the majority of tumors were positively stained (> or = 65% of the tumors) with varying intensities. Thirty-nine percent of the tumors were positively stained with the antibody vff16, and approximately half of the tumors with the antibodies vff17 and fw11.24. The expression of CD44 v6 epitopes in tumors from node-negative patients was associated with a favorable prognosis, both upon univariate and multivariate analysis. The expression of CD44 v7/8, v9 or v10 epitopes was not significantly related with relapse-free survival. Samples from node-positive patients were only examined with the antibodies vff7, vff17 and vff18. The staining with none of these antibodies was correlated with the length of relapse-free survival of the patients. Our data suggest that, generally, the usefulness of knowledge of CD44 variant expression is of limited value for assessing the risk of relapse in patients with primary breast cancer. However, the expression of exon v6 of CD44 may be a marker to identify patients with a relatively favorable prognosis in node-negative patients.

Adult↗

PubMed1999

Vitamin E status in patients with liver cirrhosis: normal or deficient?

The study aim was to compare the ratio of vitamin E to serum cholesterol with the serum vitamin E level alone as a measure of vitamin E status in patients with different degrees of liver dysfunction. Assessment of serum vitamin E and total serum cholesterol was performed in 85 patients with liver cirrhosis at Child's stage A (n = 26), B (n = 26), and C (n = 33) and 50 patients with noncirrhotic liver disease. As surrogate markers of liver function, 7alpha-hydroxycholesterol and prealbumin concentrations and the plasma prothrombin time were determined. Mean serum vitamin E concentrations in Child A, B, and C patients were 27.4%, 36.9%, and 37.3% lower, respectively, than in healthy controls (P<.01). Twelve of 26 Child A, 14 of 26 Child B, and 14 of 33 Child C patients had vitamin E deficiency with respect to the absolute values, i.e., serum levels less than 13.76 micromol/L (5% percentile of healthy controls). In contrast, only two of 26 Child A, five of 26 Child B, and five of 33 Child C patients (P<.01 for Child A/B and P<.05 for Child C) were vitamin E-deficient according to the serum vitamin E to cholesterol ratio, i.e., less than 2.86 micromol/mmol. Serum vitamin E was correlated significantly with prealbumin, 7alpha-hydroxycholesterol, and the plasma prothrombin time, but the vitamin E to cholesterol ratio was not. Correcting serum vitamin E for total serum cholesterol in patients with liver cirrhosis leads to the phenomenon of reduced serum vitamin E levels inadvertently shifted toward normal values. In patients with liver cirrhosis, the absolute vitamin E concentration correlates better with the typical clinical and biochemical findings of the disease than the vitamin E to cholesterol ratio. Therefore, a considerable number of patients with advanced liver cirrhosis might actually be vitamin E-deficient.

Adult↗

PubMed1999

Interferon/antioxidant combination therapy for chronic hepatitis C--a controlled pilot trial.

The effects of two forms of antioxidative co-therapy were analyzed in 24 interferon-alpha (IFN)-naive patients with chronic hepatitis C who were randomized to either receive IFN monotherapy (3 x 4.5 million units IFN-alpha 2a per week), (group A), or IFN and N-acetylcysteine (N-acetylcysteine (NAC) 1.800 mg/day) plus sodium selenite (400 microg/day) supplementation (group B), or treatment as in group B plus vitamin E (544 IU/day) (group C), over 24 weeks. Changes in histology, normalization of ALT, reduction of viral RNA, serum levels of glutathione, selenium, vitamin E, erythrocyte glutathione peroxidase, trolox equivalent antioxidative capacity (TEAC), thiobarbituric acid reactive substances (TBARS) and protein carbonyl groups were measured. Low baseline TEAC and elevated TBARS indicated increased oxidative stress before therapy, which was not affected by antioxidant supplementation. At the end of treatment complete responses were found in 3/8, 2/8 and 6/8 patients in groups A, B and C, respectively, but liver histology had not significantly improved. Vitamin E treated patients had a 2.4 greater chance (95% CI: 1.05-5.5) of obtaining a complete response and had significantly greater reduction in viral load (P = 0.028) than patients without vitamin E. Relapses, i.e. re-appearance of detectable hepatitis C virus (HCV) RNA and/or re-elevation of ALT-activity occurred in 7 out of the 11 responders within 6 months after termination of therapy (group A: 2/3, group B: 1/2 and group C: 4/6). Thus, no overall beneficial effect of antioxidant/IFN therapy was detected. However, the apparent trend towards a more favorable outcome with vitamin E supplementation warrants to further study this substance as an adjuvant to IFN therapy in chronic hepatitis C.

Acetylcysteine↗