EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer.

BACKGROUND: Proteolytic enzymes and their regulators have important biological roles in colorectal cancer by stimulating invasion and metastasis, which makes these factors attractive as potential prognostic biomarkers. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN) was characterised using immunohistochemistry in primary tumours from a cohort of 277 prospectively recruited colorectal cancer patients, and associations with expression of S100A4, clinicopathological parameters and patient outcome were investigated. RESULTS: One hundred and ninety-eight samples (72%) displayed positive membrane staining of the tumour cells, whereas 10 cases (4%) were borderline positive. EMMPRIN expression was associated with shorter metastasis-free, disease-specific and overall survival in both univariate and multivariate analyses. The prognostic impact was largely confined to TNM stage III, and EMMPRIN-negative stage III patients had an excellent prognosis. Furthermore, EMMPRIN was significantly associated with expression of S100A4, and the combined expression of these biomarkers conferred an even poorer prognosis. However, there was no evidence of direct regulation between the two proteins in the colorectal cancer cell lines HCT116 and SW620 in siRNA knockdown experiments. CONCLUSION: EMMPRIN is a promising prognostic biomarker in colorectal cancer, and our findings suggest that it could be used in the selection of stage III patients for adjuvant therapy.

Prognostic importance of DNA ploidy and DNA index in stage I and II endometrioid adenocarcinoma of the endometrium.

BACKGROUND: We evaluated the prognostic importance of DNA ploidy in stage I and II endometrioid adenocarcinoma (EAC) of the endometrium with a focus on DNA index. PATIENTS AND METHODS: High-resolution DNA ploidy analysis was carried out in tumor material from 937 consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) stage I and II EAC of the endometrium. RESULTS: Patients with diploid (N = 728), aneuploid tumor with DNA index ≤ 1.20 (N = 118), aneuploid tumors with DNA index >1.20 (N = 39) and tetraploid tumor (N = 52) had 5-year recurrence rates 8%, 14%, 20% and 12%, respectively. Patients with aneuploid tumor with DNA index >1.20 had a poorer 5-year progression-free survival (67%) and overall survival (72%) compared with the patients with aneuploid tumor with DNA index ≤ 1.20 (81% and 89%, respectively). Aneuploid tumors with DNA index ≤ 1.20 relapsed mainly in the vagina and pelvis, whereas aneuploid tumors with DNA index >1.20 relapsed predominantly outside pelvis. CONCLUSIONS: The recurrence risk for the patients with aneuploid tumor is higher than the patients with diploid tumor in EAC of the endometrium. Based on DNA index with cut-off 1.20, aneuploid tumors can be separated into two subgroups with different recurrence pattern and survival.

The mild inflammatory response in febrile neutropenic lymphoma patients with low risk of complications is more pronounced in patients receiving tobramycin once daily compared with three times daily.

We evaluated inflammatory markers in febrile neutropenic lymphoma patients undergoing high-dose chemotherapy with autologous stem cell support. Based on MASCC scores, our patients had a low risk of serious complications and a perspective of a benign initial clinical course of the febrile neutropenia. We also studied the impact of tobramycin given once versus three times daily on these immune markers. Sixty-one patients participating in a Norwegian multicentre prospective randomized clinical trial, comparing tobramycin once daily versus three times daily, given with penicillin G to febrile neutropenic patients, constituted a clinically homogenous group. Four patients had bacteraemia, all isolates being Gram-positive. Thirty-two patients received tobramycin once daily, and 29 patients received tobramycin three times daily. Blood samples were taken at the onset of febrile neutropenia and 1-2 days later. All samples were frozen at -70 °C and analysed at the end of the clinical trial for C-reactive protein (CRP), procalcitonin (PCT), complement activation products, mannose-binding lectin (MBL) and 17 cytokines. We found a mild proinflammatory response in this series of patients. CRP was non-specifically elevated. Ten patients with decreased MBL levels showed the same mild clinical and proinflammatory response. Patients receiving tobramycin once daily showed a more pronounced proinflammatory response compared with patients receiving tobramycin three times daily. Overall, febrile neutropenic cancer patients with a benign clinical course show a mild proinflammatory immune response.

The role of surgery in the second relapse of epithelial ovarian cancer. Selection criteria, morbidity and survival outcome.

BACKGROUND: The aim of this study was to investigate the benefit of cytoreductive surgery (CS) and palliative surgery (PS) because of bowel obstruction in the second relapse (SR) in epithelial ovarian cancer. METHODS: A retrospective population-based study on recorded information from 490 consecutive patients treated at the Norwegian Radium Hospital during 1985-2001 for their SR. In all, 80 had surgery, 28 and 52 of which had their tertiary surgery (TS) and secondary surgery (SS), respectively and 410 were treated with chemotherapy or other therapy. RESULTS: Median survival time (MST) was nine months for the last group. Complete optimal cytoreduction (COC) was achieved in 56% of the patients operated with CS. At SS and TS 33% and 38%, respectively, achieved COC. MST was 46 versus seven months for 0 versus > 2 cm residual disease. MST for the CS and PS was 31 versus five months, respectively. Twenty-eight percent with CS experienced complications versus 42% with PS including two deaths. On univariate analysis initial stage, residual tumor at first relapse, residual tumor at SR, treatment-free interval from primary treatment to first relapse (TFI 0-1), type of chemotherapy at SR, WHO performance status, ascites, elevated CA 125 values, number of lesions, localization of tumor and tumor size were found to be significant prognostic factors for survival in the surgery group. CONCLUSIONS: The combination of COC, TFI 0-1 > or = 24 months, CA 125 < or = 35, < or = 3 tumor lesions and WHO 1 performance criteria identifies a group of patients with the best overall survival in SR.

Disseminated tumour cells as a prognostic biomarker in colorectal cancer.

BACKGROUND: The study was performed to determine detection rate and prognostic relevance of disseminated tumour cells (DTC) in patients receiving curatively intended surgery for colorectal cancer (CRC). METHODS: The study population consisted of 235 patients with CRC prospectively recruited from five hospitals in the Oslo region. Bone marrow (BM) aspirates were collected at the time of surgery and the presence of DTC was determined by two immunological methods; immunomagnetic selection (using an anti-EpCAM antibody) and immunocytochemistry (using a pan-cytokeratin antibody). Associations between the presence of DTC and metastasis-free, disease-specific and overall survival were analysed using univariate and multivariate methods. RESULTS: Disseminated tumour cells were detected in 41 (17%) and 28 (12%) of the 235 examined BM samples by immunomagnetic selection and immunocytochemistry, respectively, with only five samples being positive with both methods. The presence of DTC was associated with adverse outcome (metastasis-free, disease-specific and overall survival) in univariate and multivariate analyses. CONCLUSION: The presence of DTC was associated with adverse prognosis in this cohort of patients curatively resected for CRC, suggesting that DTC detection still holds promise as a biomarker in CRC.

Palliative interventions and prognosis in patients with advanced esophageal cancer.

In a retrospective review, in order to describe the palliative care and prognosis of patients with advanced cancer of the esophagus, the clinical characteristics and the treatment modalities applied were explored in relation to survival and symptom relief for 261 patients treated without curative potential. The data were obtained from a study of all patients with cancer of the esophagus treated at the Norwegian Radium Hospital in the 10-year period from 1990 to 1999. Medical data of the patients were reviewed and missing clinical information was retrieved from local hospitals and general practitioners. The patients were divided into three groups based upon the overall survival from start of treatment to death. Survival ≤3 months is in this paper, defined as 'short,' while survival > 6 months is defined as 'long.' Median survival for the total group of patients was 4 months. The 1-, 2-, and 3-year survival was 8%, 3%, and 1%, respectively. Patients with short survival (n= 107) had more advanced disease, lower performance status, and more dysphagia, weight loss, and pain and used more analgesics than patients with long survival (n= 91). Tumor characteristics such as localization, tumor length, and histology were not significantly associated with survival. This result was confirmed in a logistic regression analysis (with backward stepwise elimination) including sex, age, clinical stage, tumor length, tumor localization, histology, performance status, dysphagia, weight loss, and pain, where clinical stage, performance status, weight loss, and pain were included in the final model. A large variety of first-line palliative treatments were applied within the studied time period; external radiotherapy ± brachytherapy (n= 149), brachytherapy alone (n= 44), endoluminal stent (n= 28), laser evaporization (n= 8), chemotherapy (n= 5), and best supportive care only (n= 27). There were no clear differences in the effect on dysphagia between the modalities. Fourteen percent of the patients had treatment related complications. In conclusion, symptoms, performance status, and use of analgesics seemed to better prognosticate survival than tumor characteristics other than stage of disease. Our study reveals that knowledge about prognostic factors is crucial for the choice of palliative treatment. Even though all of the different treatment modalities seemed to provide relief of dysphagia, several other factors should be considered when deciding which treatment modality to offer. The time to onset of relief, duration of response, level of complications, and time spent in hospital should be a part of the decision-making process when selecting the appropriate treatment.

The role of secondary cytoreduction in the management of the first relapse in epithelial ovarian cancer.

BACKGROUND: The aim of this study was to investigate the benefit of secondary cytoreduction (SCR) in the first relapse in epithelial ovarian cancer and to attempt to define selection criteria for SCR. PATIENTS AND METHODS: A retrospective population-based study on recorded information from 789 patients treated at the Norwegian Radium Hospital during 1985-2000 for their initial recurrence. In all, 217 had SCR and 572 were treated with chemotherapy alone. RESULTS: Median survival time (MST) was 1.1 years for the chemotherapy group. Complete optimal cytoreduction (COC) was achieved in 35% of all 217 patients, in 49% of the patients operated with debulking intent and in 52% if bowel surgery was done with debulking intent. MST was 4.5 versus 0.7 years for 0 versus>2 cm residual disease, respectively. Residual disease after SCR, treatment-free interval (TFI) and age were found to be prognostic factors for overall survival (OS) in multivariate analysis. Localised tumour was found to be the only significant factor to predict COC. CONCLUSIONS: SCR followed by chemotherapy gives a clear survival benefit compared with chemotherapy and should be offered when the tumour is localised. The combination of COC, TFI >24 months and age

Is the watch and wait approach adequate after comprehensive surgical staging in invasive stage I epithelial ovarian cancer? The Norwegian Radium Hospital experience.

OBJECTIVES: The aim of this study on stage I epithelial ovarian cancer (EOC) was to see if our different treatment policies after 1995, when lymph node staging and paclitaxel were introduced, have affected the survival, try to define risk groups for relapse and who should get adjuvant chemotherapy (AC). METHODS: A retrospective study based on record information from all patients with invasive EOC stage I operated at the Norwegian Radium Hospital (NRH) 1984-2001, in total 252 patients. RESULTS: Total 5-year survival was 83 and 82%, respectively, in both time periods. We found age and histology to be significant prognostic factors for overall survival (OS) (p < 0.01). From 1995 survival was significantly better for those who had been properly staged than for the others (p = 0.02), with a 5-year survival rate of 87 vs 64%. Those who did not get chemotherapy but were staged, had a significantly better overall survival than those who were not (p = 0.02), with a 5-year survival of 93 vs 77%. In the period 1995-2001 the patients who received no adjuvant treatment lived longer than those who underwent chemotherapy and/or radiotherapy (p = 0.03). In the first period 17% had no adjuvant treatment vs 58% in the last. Patients in a high-risk group getting AC had a tendency toward better survival than those who did not (p = 0.08). CONCLUSIONS: Patients with Stage I low and medium risk EOC do not need AC if properly staged. For the high-risk group the optimal AC has not yet been established.

Improved survival for stage IIIC ovarian cancer patients treated at the Norwegian Radium Hospital between 1984 and 2001.

BACKGROUND: The aim of this study was to evaluate the treatment of FIGO Stage IIIC patients who were primarily treated completely or partially at the Norwegian Radium Hospital (NRH) during a 15-year period in order to discover possibilities for improvement of prognosis of advanced ovarian cancer. MATERIALS AND METHOD: A retrospective study based on record information from all patients with epithelial ovarian cancer Stage IIIC treated at NRH from 1985-2000, in total 776 patients. RESULTS: We found age, amount of residual tumour after surgery for primary treatment and type of chemotherapy to be the most significant prognostic factors for overall survival. During the last 5-year period primary surgery was increasingly centralised, and surgery was improved with lymph node staging and use of paclitaxel. Survival was significantly better during the last 5-year period and after macroscopic radical surgery. Also progression-free survival was better with no macroscopic tumour remaining. INTERPRETATION: Improved survival during the last 5-year period is partly attributed to improved surgery and partly to the addition of paclitaxel. We believe that further centralisation of primary surgery for advanced ovarian cancer can contribute to a better prognosis.

Ovarian cancer stage IIIC. Consequences of treatment level on overall and progression-free survival.

BACKGROUND: Maximum cytoreduction at primary surgery has been found to be one of the strongest prognostic factors for survival of ovarian cancer. The aim of the study was to investigate the influence of hospital level (primary vs secondary care centre), number and timing of surgery and chemotherapy on how radical the surgery was at primary treatment of epithelial ovarian cancer Stage IIIC. MATERIAL AND METHODS: A retrospective study based on record information from all patients with epithelial ovarian cancer Stage IIIC treated at the Norwegian Radium Hospital (NRH) 1985-2000, in total 776, subdivided into four groups: 1) Local primary surgery, no direct re-operation at NRH, no interval debulking; 2) local primary surgery, no direct re-operation, but interval debulking after 3-4 courses of chemotherapy at NRH; 3) local primary surgery, direct re-operation at NRH, no interval debulking; 4) primary surgery at NRH. Lymph node biopsies at re-operation in early stages and upgrading of stage where necessary were registered. RESULTS: Whether surgery was radical or not was an independent prognostic factor for overall and progression-free survival. The treatment group was an independent prognostic factor for overall, but not for progression-free survival. Group 3 had significantly the best overall and progression-free survival (p = 0.01 and 0.05). For macroscopically radical surgery both overall and progression-free survival were found significantly better for groups 3, 4 and 1 than for group 2. Most lymph node biopsies were performed during the last period and 28% were upgraded from Stage I and II to IIIC. More patients were referred for primary surgery at NRH during the last 5-year period during which overall survival and time to progression were significantly better. INTERPRETATION: Whether primary surgery is radical or not is a significant prognostic factor for survival and primary surgery is best performed by specialists in gynaecological oncology.

Prognostic factors in ovarian carcinoma stage III patients. Can biomarkers improve the prediction of short- and long-term survivors?

The aim of the study was to determine if biomarker expression could help discriminate between short-term and long-term survivors in women with advanced ovarian cancer. Fifty-one patients with stage III ovarian cancer were selected for the study, which included 28 short-term survivors (death from ovarian cancer within 18 months) and 23 long-term survivors (alive for more than 5 years). There was no difference between the two groups with respect to FIGO substage, age, World Health Organization score, and first-line platinum therapy. Classic clinical pathologic parameters were examined together with p53, Bcl-2, Ki-67, PDGFRalpha, P-glycoprotein, BRCA1, and DNA ploidy. Immunohistochemistry was used for scoring biomarker expression and image cytometry for DNA ploidy. All patients had primary debulking surgery followed by first-line platinum therapy. On multivariate analysis, the presence of ascites, debulking surgery and repeat laparotomy, clear-cell histology, elevated CA125, and high Ki-67 score were all found to be of prognostic importance. The long-term survivors were characterized by primary optimal cytoreduction surgery (<1 cm residual disease), attempt at maximal tumor debulking by experienced gynecological oncologic surgeons, and the absence of ascites. Normal CA125 level before platinum therapy and negative Ki-67 expression also predicted a more favorable prognosis.

DNA- versus RNA-based methods for human papillomavirus detection in cervical neoplasia.

OBJECTIVE: To compare DNA-based and mRNA-based methods for detection of high-grade cervical neoplasia in Norway. METHODS: HPV prevalence was analyzed in 383 women with positive index cytology, selected from gynecology clinics. All patients were investigated by a new PAP smear, histology, and two commercially available HPV tests: Hybrid Capture II (Digene, Gaithersburg, MD) and the Pre Tect HPV-Proofer (NorChip AS). Cases with positive DNA test and negative mRNA test and cases with high-grade histology and negative HPV tests were retested with PCR and sequencing. We regarded the infection as latent or transient if sequencing revealed an HPV type included in both assays. RESULTS: High-risk HPV was detected in 99.7% of the histological confirmed high-grade lesions (CIN2+) (290/291). The DNA test was positive in 95% (275/291), and the mRNA test was positive in 77% (225/291) of the histological confirmed high-grade lesions. All invasive carcinomas were mRNA positive. The DNA test was significantly more often positive in benign and low-grade lesions, some of which were found to be false positive due to cross-contamination with unrelated types. High-grade histology was detected in 83% of women with normal cytology and positive mRNA test. Latent or transient infections were detected in 11 low-grade and 12 high-grade preinvasive lesions. Sequencing revealed high-risk HPV types included only in the DNA test in 35 high-grade preinvasive lesions, HPV 52 and 58 were the most prevalent HPV types. CONCLUSIONS: These HPV tests have the potential to improve the detection rate of high-grade cervical neoplasia, with some limitations. The mRNA test seems to be more appropriate for risk-evaluation. Larger scale, population based studies are necessary to evaluate the predictive values of HPV testing in Norway.

Twenty years experience with semen cryopreservation in testicular cancer patients: who needs it?

PURPOSE: To evaluate the role of semen cryopreservation (SCP) in the fertility saving management of testicular cancer (TC) patients, treated at the Norwegian Radium Hospital between 1983 and 2002. PATIENTS AND METHODS: 422 of 1388 newly diagnosed TC patients had SCP All patients were followed up for post-treatment paternity. RESULTS: During the 20 years study period, by 2002 an increasing percentage of patients had pre-treatment SCP, reaching 43% after 1994. Twenty-nine (7%) of the 422 patients with SCP had used their frozen semen for assisted reproductive techniques (ART) at least once to achieve fatherhood. Pregnancies were achieved in 16 of these patients' partners, but two of these pregnancies ended in abortions. 67(17%) of 393 men with SCP fathered at least one child without use of frozen semen. The comparable figures for those without SCP were 205 out of 966(21%). Twenty years after orchiectomy the cumulative incidence of first post-treatment fatherhood was 47% for the 393 patients who had SCP but did not use it for ART, and 34% for the 966 patients without SCP (p=0.12). CONCLUSION: If offered, about 50% of the young and middle-aged patients newly diagnosed with TC are interested in pre-treatment SCP. Though our study reveals that a considerable number of TC patients referred to SCP, achieve fatherhood without the use of frozen semen, the psychological impact of pre-treatment cryopreservation is undeniable. Furthermore, for some TC survivors ART with cryopreserved sperm offers the only chance of post-treatment paternity.

Iron status among 3005 women aged 20-55 years in Central Norway: the Nord-Trøndelag Health Study (the HUNT study).

OBJECTIVE: To describe the iron status of Norwegian women of fertile age, to show the prevalence of iron-deficiency anemia and iron overload, and to demonstrate possible factors connected to and/or influencing iron status. MATERIAL AND METHODS: The diagnostic criteria were: (a) anemia: hemoglobin (Hb) < 120, < 117, or < 115 g/l; (b) depleted iron stores: serum ferritin (SF) < 10 or 12 microg/l; iron-deficiency anemia: (a)+(b). Iron overload: SF > or = 110 microg/l. The study was conducted in Central Norway where a total of 3005 women aged 20 to 55 years were enrolled in a health survey program (the HUNT Study). None of the women were pregnant and none had been blood donors in the two previous years. RESULTS: Median SF was 31.0 microg/l. Depleted iron stores were present in 10.9 and 15.1%, respectively. The Hb 2.5%tile among the iron-replete women was 117 g/l. With this cut-off value, anemia was present in 4.7% and iron-deficiency anemia in about 3%. Iron overload was present among 5.2%, and homozygous primary hemochromatosis among 0.4%. CONCLUSIONS: The prevalence of iron-deficiency anemia was relatively low and similar to that found earlier in small groups of Norwegian women. The prevalence is comparable with results from other developed countries.

Iron status in a group of Norwegian children aged 6-24 months.

UNLABELLED: An adequate iron status is of vital importance for health and development in infancy and early childhood. Iron status was evaluated in a group of full-term Norwegian children followed longitudinally, at the ages of 6 mo (n = 278), 12 mo (n = 249) and 24 mo (n = 231) by measuring haemoglobin (Hb), mean cell volume (MCV) and serum ferritin. At 6, 12 and 24 mo of age, 3, 10 and 12%, respectively, had iron deficiency anaemia (IDA) defined as Hb <110 g/l in combination with ferritin <15 microg/l. With more restrictive criteria for defining IDA (Hb <110 g/l or <105 g/l in combination with ferritin <12 microg/l), the prevalence decreased to 1-2% at 6 mo and 2-5% at 12 and 24 mo of age. If children with a history of fever in the previous month were excluded, the proportion of children with depleted iron stores (ferritin <10 microg/l) increased from 2 to 3% at 6 mo, from 5 to 7% at 12 mo and from 9 to 13% at 24 mo. CONCLUSION: Mild iron deficiency anaemia exists among otherwise healthy Norwegian infants and toddlers. The prevention and early treatment of iron deficiency should be a priority for the child health services.

Dietary habits among patients with atopic dermatitis.

OBJECTIVE: To evaluate the dietary habits among adult patients with moderate to severe atopic dermatitis and relate intake to clinical symptoms. DESIGN: Data were obtained from a clinical trial. SETTING: Five departments of dermatology at Norwegian University hospitals. SUBJECTS: Outpatients, 46 men (median age 27 y) and 92 women (median age 28 y). METHOD: A quantitative food frequency questionnaire was filled in before attending the clinical trial. The results were compared to the diet of age- and sex-matched reference groups. RESULTS: Male patients had higher content of refined sugar in their diet than reference men (P=0.014). Among female patients, the intake of saturated fatty acids was higher (P=0.049), whereas the intake of very long-chain n-3 fatty acids was lower (eicosapentaenoic acid, P=0.032, docosahexaenoic acid, P=0.017) than in the reference group. In both genders, more patients than reference subjects had vitamin D intake below recommended level. Furthermore, the female patients had significantly lower intake of fruit compared to the reference group (P=0.002). No correlation was found between nutrient intake of the patients and their clinical scores. CONCLUSIONS: The patients's diet were fairly similar to the diet of reference groups. The intake of vitamin D and very long-chain n-3 fatty acids was low, especially among female patients. Furthermore, we could not detect any association between dietary habits and clinical status. European Journal of Clinical Nutrition (2000) 54, 93-97

Plasma homocysteine concentration related to diet, endothelial function and mononuclear cell gene expression among male hyperlipidaemic smokers.

BACKGROUND: Elevated plasma concentration of homocysteine is an independent risk factor for development of cardiovascular diseases. MATERIALS AND METHODS: We evaluated potential links between homocysteine and atherothrombogenesis by relating the plasma concentration of homocysteine to (i) dietary antioxidants and omega-3 fatty acids (and determined influence of intervention with antioxidants or omega-3 fatty acids); (ii) markers of endothelial cell function; and (iii) peripheral blood mononuclear cell mRNA levels. RESULTS: We observed an inverse relationship between the plasma homocysteine concentration and dietary intake of vegetables, vitamin C and beta-carotene and between homocysteine and the serum concentration of folate, vitamin B12 and omega-3 fatty acids. Intervention with antioxidants or omega-3 fatty acids did not affect plasma homocysteine concentration. The plasma levels of cysteinylglycine and vitamin B12 correlated positively with circulating E-selectin and VCAM-1, respectively, whereas folate in serum and blood correlated negatively with P-selectin. A negative correlation was found between the concentrations of homocysteine and von Willebrand factor. Negative and positive correlations were found between plasma homocysteine and the mononuclear cell mRNA levels of peroxisome proliferator activated receptor delta (PPAR delta) and c-myc respectively. A negative correlation was also found between plasma homocysteine and mononuclear cell mRNA levels of the proteoglycan serglycin. Homocysteine was not correlated with serum activity of glutathione peroxidase or with the mRNA level of glutathione peroxidase in mononuclear cells. CONCLUSION: The plasma homocysteine level was negatively correlated with dietary intake of vegetables, including vitamins C and E, and serum omega-3 fatty acids, whereas supplementation with antioxidants or omega-3 fatty acids did not affect plasma homocysteine concentration. Homocysteine was not associated with circulating adhesion molecules or increased procoagulant activity, but homocysteine may alter mononuclear cell gene expression. Cysteine showed no significant correlation with these parameters.

Peroxidation of LDL from combined-hyperlipidemic male smokers supplied with omega-3 fatty acids and antioxidants.

The effects of marine omega-3 polyunsaturated fatty acids (FAs) and antioxidants on the oxidative modification of LDL were studied in a randomized, double-blind, placebo-controlled trial. Male smokers (n = 41) with combined hyperlipidemia were allocated to one of four groups receiving supplementation with omega-3 FAs (5 g eicosapentaenoic acid and docosahexaenoic acid per day), antioxidants (75 mg vitamin E, 150 mg vitamin C, 15 mg beta-carotene, and 30 mg coenzyme Q10 per day), both omega-3 FAs and antioxidants, or control oils. LDL and human mononuclear cells were isolated from the patients at baseline and after 6 weeks of supplementation. LDL was subjected to cell-mediated oxidation by the patients' own mononuclear cells, as well as to Cu(2+)-catalyzed and 2,2'-azobis-(2-amidinopropane hydrochloride) (AAPH)-initiated oxidation. Extent of LDL modification was measured as lag time, the formation rate of conjugated dienes (CDs), the maximum amount of CDs formed, formation of lipid peroxides, and the relative electrophoretic mobility of LDL on agarose gels. Dietary supplementation with omega-3 FAs increased the concentration of total omega-3 FAs in LDL and reduced the concentration of vitamin E in serum. The omega-3 FA-enriched LDL particles were not more susceptible to Cu(2+)-catalyzed, AAPH-initiated, or autologous cell-mediated oxidation than control LDL. In fact, enrichment with omega-3 FAs significantly reduced the formation rate of CDs when LDL was subjected to AAPH-induced oxidation. Supplementation with moderate amounts of antioxidants significantly increased the concentration of vitamin E in serum and increased the resistance of LDL to undergo Cu(2+)-catalyzed oxidation, measured as increased lag time, reduced formation of lipid peroxides, and reduced relative electrophoretic mobility compared with control LDL. Supplementation with omega-3 FAs/antioxidants showed oxidizability of LDL similar to that of control LDL and omega-3 FA-enriched LDL. In conclusion, omega-3 FAs neither rendered the LDL particles more susceptible to undergo in vitro oxidation nor influenced mononuclear cells' ability to oxidize autologous LDL, whereas moderate amounts of antioxidants protected LDL against oxidative modification.

Effects of partially hydrogenated fish oil, partially hydrogenated soybean oil, and butter on hemostatic variables in men.

We have compared the effects of partially hydrogenated fish oil (PHFO diet), partially hydrogenated soybean oil (PHSO diet), and butterfat (butter diet) on fibrinolytic and coagulation variables in 31 young men. The three test margarines, which contributed 78% of total fat in the diets, contained 70% butterfat, PHSO, or PHFO, each with 30% of soybean oil. Fat provided approximately 35% of energy, and the content of trans-fatty acids was 0.9%, 8.5%, and 8.0% of energy in the butter diet, PHSO diet, and PHFO diet, respectively. All diets contained 420 mg cholesterol per 10 megajoules per day. All subjects consumed all three test diets for 3 weeks, in a random order (crossover design). The PHSO diet resulted in higher levels of plasminogen activator inhibitor type 1 antigen and plasminogen activator inhibitor type 1 activity than the two other test diets. Fibrinogen increased on the butter diet compared with the PHFO diet. No significant differences in the levels of factor VII, fibrinopeptide A, D-dimer, tissue plasminogen activator or beta-thromboglobulin were observed between the three test diets. The PHFO and the PHSO diets have previously been shown to result in higher levels of Lp(a) compared with the butter diet. The present findings indicate that PHSO has unfavorable antifibrinolytic effects relative to PHFO and butter and that butter may be procoagulant relative to PHFO. More controlled studies are needed to assess definitely the impact of different hydrogenated fats on risk of coronary heart disease.