Can serum human epididymis protein 4 (HE4) support the decision to refer a patient with an ovarian mass to an oncology hospital?

INTRODUCTION: The value of serum human epididymis protein 4 (HE4) in guiding referral decisions in patients with an ovarian mass remains unclear, because the majority of studies investigating HE4 were performed in oncology hospitals. However, the decision to refer is made at general hospitals with a low ovarian cancer prevalence. We assessed accuracies of HE4 in differentiating benign or borderline from malignant tumors in patients presenting with an ovarian mass at general hospitals. METHOD: Patients with an ovarian mass were prospectively included between 2017 and 2021 in nine general hospitals. HE4 and CA125 were preoperatively measured and the risk of malignancy index (RMI) was calculated. Histological diagnosis was the reference standard. RESULTS: We included 316 patients, of whom 195 had a benign, 39 had a borderline and 82 had a malignant ovarian mass. HE4 had the highest AUC of 0.80 (95%CI 0.74-0.86), followed by RMI (0.71, 95%CI 0.64-0.78) and CA125 (0.69, 95%CI 0.62-0.75). Clinical setting significantly influenced biomarker performances. Applying age-dependent cut-off values for HE4 resulted in a better performance than one cut-off. Addition of HE4 to RMI resulted in a 32% decrease of unnecessary referred patients, while the number of correctly referred patients remained the same. CONCLUSION: HE4 is superior to RMI in predicting malignancy in patients with an ovarian mass from general hospitals. The addition of HE4 to the RMI improved HE4 alone. Although, there is still room for improvement, HE4 can guide referral decisions in patients with an ovarian mass to an oncology hospital.

Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients.

Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen. Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.

Modulation of plasma fibrinogen levels by ciprofibrate and gemfibrozil in primary hyperlipidaemia.

An elevated plasma fibrinogen level is increasingly accepted as an independent risk indicator of cardiovascular disease. This has enhanced the interest in identifying agents that can normalize elevated plasma fibrinogen levels. One group of agents with this capacity are the fibric acid derivatives, e.g. ciprofibrate and gemfibrozil. We studied fibrinogen levels after 12 weeks of treatment with ciprofibrate (n = 48) and gemfibrozil (n = 51) in hypercholesterolenic patients. The correlation of the decrease in fibrinogen with lipid lowering and the contribution of the acute phase and genetic polymorphisms to this decrease were also evaluated. After 12 weeks of treatment, the fibrinogen levels were significantly decreased (p < 0.0005) with both drugs, although the decrease in the ciprofibrate group (mean 3.4 g/l pre-treatment to 2.4 g/l after 12 weeks) was larger than in the gemfibrozil group (mean 3.4 g/l to 3.0 g/l). The lipid lowering effect was comparable for the two drugs but there was no correlation for either ciprofibrate or gemfibrozil between the lipid lowering and the magnitude or the velocity of the fibrinogen lowering effect. An attenuation of the major regulatory mechanism of plasma fibrinogen levels, the acute phase reaction, was invoked as the underlying mechanism. However, pre-treatment C-reactive protein levels were not increased and did not change after treatment. Moreover, no effects of the polymorphisms of the fibrinogen beta-gene on the decrease of the plasma fibrinogen levels were observed. This suggests that a new, as yet unknown, mechanism is involved in fibrinogen lowering by fibrates.

Magnesium pyridoxal-5'-phosphate glutamate, "A vitamin B6 derivative", does not affect lipoprotein levels in patients with familial hypercholesterolaemia.

OBJECTIVE: In this double-blind, randomized, placebo-controlled, dose-finding study we assessed the short-term efficacy and safety of increasing dosages of magnesium pyridoxal-5'-phosphate glutamate (MPPG) compared to placebo in patients with familial hypercholesterolaemia (FH). Twenty-three patients of either sex, over the age of 18 years and suffering from heterozygous FH, were treated with MPPG for a period of 16 weeks. RESULTS: Baseline characteristics and lipoprotein profiles of the patients were comparable in the two treatment groups. Overall compliance was 90%. Neither after the first 8 weeks treatment period with 450 mg MPPG daily nor after the second 8 weeks treatment period with 600 mg MPPG daily were statistically significant changes in plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol or triglyceride levels observed between the treatment and placebo groups. Plasma levels of lipoprotein (Lp)(a), apolipoprotein (apo) A1, apo B100, very low density lipoprotein (VLDL) cholesterol and VLDL triglyceride also did not change. CONCLUSION: Although it has been demonstrated that MPPG improves lipoprotein levels in patients with different forms of dyslipidaemia, MPPG is not effective for the treatment of FH patients.

Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia.

BACKGROUND: Familial combined hyperlipidaemia (FCH), characterized by elevated very-low-density lipoprotein (VLDL) and/or low-density lipoprotein (LDL), is associated with an increased prevalence of premature cardiovascular disease. Therefore, lipid-lowering is frequently indicated. METHODS: We evaluated in a parallel, double-blind randomized fashion the effect of gemfibrozil (1200 mg/day) (n = 40) or simvastatin (20 mg/day) (n = 41) on lipids, apolipoprotein-B (apo-B)-containing lipoproteins, apo-CIII and lipoprotein(a) [Lp(a)], in 81 well-defined FCH patients. RESULTS: While both drugs lowered plasma cholesterol and triglyceride levels, gemfibrozil lowered plasma triglycerides more effectively by reduction of triglycerides in VLDL and LDL, whereas simvastatin was more effective in its reduction of total plasma cholesterol by exclusively decreasing LDL cholesterol. High-density lipoprotein (HDL) increased to an equal extent on both therapies. Total serum apo-B levels were reduced with both drugs; however, gemfibrozil decreased apo-B only in VLDL + IDL, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL. In keeping with a more effective reduction of VLDL particles, a more pronounced reduction of apo-CIII also was observed after gemfibrozil, which correlated with the reduction in plasma triglycerides. Baseline concentrations of Lp(a) showed a wide range in both treatment groups. Median Lp(a) levels increased after simvastatin, but were not affected by gemfibrozil. CONCLUSION: Both therapies exhibited their specific effects, although none of the drugs alone completely normalized the lipid profiles of these patients with FCH. Therefore, the choice of treatment should be based on the most elevated lipoprotein fraction, and in some cases a combination of the two drugs may be indicated.

Ciprofibrate versus gemfibrozil in the treatment of primary hyperlipidaemia.

The efficacy and short-term safety of ciprofibrate and gemfibrozil were compared in a 12-week, double-blind, randomised study. One-hundred-and-ten primary, type II hyperlipidaemic patients were randomised to receive either ciprofibrate, 100 mg/day once daily, or gemfibrozil, 1200 mg/day twice daily. Treatment efficacy was measured by complete lipid and lipoprotein profiles and by plasma fibrinogen levels. Tolerability was assessed by drug compliance and safety was evaluated by laboratory safety parameters, physical examination and evaluation of adverse events. Mean reductions of plasma TC and low density lipoprotein cholesterol levels were similar in the two treatment groups. In contrast, the mean relative reduction of plasma total triglyceride and very low density lipoprotein triglyceride levels was significantly higher in patients receiving gemfibrozil as compared with ciprofibrate (P < 0.05). The absolute reduction of the last two parameters was higher in the ciprofibrate group compared with the gemfibrozil group; furthermore, the mean concentrations of these parameters were within normal limits at the end of the study. The clinical relevance of the statistically significant difference mentioned should, therefore, be questioned. Ciprofibrate therapy significantly reduced (-8.33%) and gemfibrozil therapy significantly increased (+6.97%) plasma fibrinogen levels (P < 0.001 compared with baseline in each case). Adverse events were rare, mild and equally distributed between the two treatment groups. Laboratory safety parameters did not show any significant changes. Ciprofibrate and gemfibrozil have comparable short-term efficacy and safety profiles. Furthermore, ciprofibrate reduces fibrinogen levels and benefits from a once daily regimen.

Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia.

The safety, tolerability, and efficacy of a 12-wk treatment with pravastatin, 5, 10, and 20 mg/d, was evaluated in 72 children with heterozygous familial hypercholesterolemia (FH) in a double-blind, randomized and placebo-controlled study. The results show that pravastatin was well tolerated and that adverse events were mild and equally distributed among the three treatment groups. Plasma total and LDL cholesterol levels were significantly reduced in all pravastatin treatment groups, in comparison with the control group; -24.6% (-28.1 to 21.0) and -32.9% (-37.0 to -28.6), for mean change and 95% confidence interval, respectively. In four children plasma LDL cholesterol levels were reduced within normal limits for sex and age. HDL cholesterol increased in the pravastatin 20-mg group, +10.8% (+3.4 to +18.8), whereas plasma apo B100 and very LDL (VLDL) cholesterol levels were reduced within all pravastatin-treated groups -26.8% (-31.2 [corrected] to -21.7) and -24.5% (-35.0 to -12.3). These data show that short-term pravastatin treatment of children with FH is safe and effective, although long-term dose titration studies with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors need to be performed, to reduce plasma LDL cholesterol levels below a predefined level. The results of these studies have to be awaited before new treatment strategies are to be considered in these children.

Gemfibrozil treatment of the high triglyceride-low high-density lipoprotein cholesterol trait in men with established atherosclerosis.

OBJECTIVE: To study the short-term efficacy, tolerability and safety of the treatment with gemfibrozil 600 mg twice daily or placebo in male patients with established atherosclerosis, with a lipid profile matching the 'high triglyceride-low high-density lipoprotein (HDL) cholesterol trait'. DESIGN: Double-blind randomized placebo controlled prospective trial. SETTING: Amsterdam Lipid Research Clinic at the Academic Medical Centre of the University of Amsterdam and the Slotervaart Training Hospital affiliated to the University of Amsterdam, Amsterdam, the Netherlands. SUBJECTS: Thirty-five male patients, age 30-70, with established atherosclerosis and the high triglyceride-low HDL cholesterol trait. MAIN OUTCOME MEASURES: Plasma total cholesterol, triglycerides, lipoproteins, apolipoproteins A1 and B100, clinical and laboratory safety parameters. RESULTS: Seventeen patients in the gemfibrozil group and 16 patients in the placebo group completed the study period. Compliance was considered adequate. Mean (+/- standard deviation) plasma HDL cholesterol levels increased 20.3% (+/- 12.22) from 0.82 to 0.99 mmol L-1 in the gemfibrozil group against 9.9% (+/- 18.31) from 0.79 to 0.87 mmol L-1 in the placebo group (P = 0.001). Mean plasma triglyceride level fell 49.5% (+/- 14.27) from 3.65 to 1.82 mmol L-1 in the gemfibrozil group against an increase of 13.6% (+/- 40.31) from 3.62 to 4.01 mmol L-1 in the placebo group (P < 0.001). Although plasma HDL cholesterol and triglyceride levels improved in all patients, normalization of these lipoproteins was only observed in approximately half of them. Plasma total and low-density lipoprotein (LDL) cholesterol levels, as well as plasma levels of apolipoprotein (apo) A1, B100 and lipoprotein [Lp(a)], did not show significant alterations compared to the placebo. All safety parameters were comparable between the two groups and remained within the reference limits. Gemfibrozil was well tolerated during treatment. Minor inconveniences were equally distributed between the two treatment groups. CONCLUSIONS: Gemfibrozil is an effective and safe drug in patients with coronary heart disease (CHD) and the high triglyceride-low HDL cholesterol trait.

Clinical experience with a new antithrombotic (dermatan sulfate) in chronic hemodialysis patients.

Dose finding studies with a new antithrombotic (dermatan sulfate) for the prevention of clot formation in the extracorporeal circuit were performed in chronic hemodialysis patients in comparison with standard heparin treatment. Dermatan sulfate (DS), which inhibits the coagulation via the heparin cofactor II pathway, was given in single predialysis injections, immediately before commencement of the dialysis procedures, in dosages ranging from 2 mg/kg to 6 mg/kg body weight. In our pilot study, an open non comparative study in patients using plate type dialyzers, we observed moderate clot formation in the extracorporeal circuit. In our second study, with a randomized heparin-controlled design in patients with plate type dialyzers, still significant clot formation occurred in the extracorporeal circuit. In the third study, in chronic hemodialysis patients using a cuprophane hollow fiber dialyzer, we also investigated the addition of a small bolus of standard heparin (20 I.U./kg body weight) to the injection of DS. A single bolus injection of 6 mg/kg, with or without the addition of a bolus of standard heparin, had a comparable efficacy as standard heparin treatment. No major bleeding events were encountered in the studies and DS had a reduced effect on the activated partial thromboplastin time as compared to standard heparin. In conclusion, these results suggest that DS in a dose of 6 mg/kg, with or without a small dose of standard heparin, given as single predialysis bolus injections, appears to be an effective alternative to standard heparin and, in addition, it may simplify the anticoagulant administration protocol.

Prevention of deep vein thrombosis following total hip replacement by low molecular weight heparinoid.

We assessed the safety and efficacy of the novel low molecular weight heparinoid Lomoparan (Org 10172) for the prevention of deep-vein thrombosis in patients undergoing elective total hip replacement in a randomized, placebo-controlled, double-blind trial in 197 consecutive patients. The heparinoid (750 anti-factor Xa-units, s.c., b.i.d.) was administered to 97 patients and 99 patients received placebo. Study medication was started preoperatively and continued for 10 days. Efficacy was assessed by bilateral phlebography at day 10, postoperatively. The incidence of deep-vein thrombosis was 56.6% and 15.5% respectively in the placebo and heparinoid treated patients (incidence reduction: 74%; P less than 0.001). This reduction was observed both for proximal-vein thrombosis (25% to 8%; P less than 0.005) and isolated calf-vein thrombosis (31% to 7%; P less than 0.001). No major hemorrhage was observed. The number of red-cell units transfused and drain-fluid loss were comparable for the two study groups. Six patients in the heparinoid group and none in the control group developed minor wound hematomas (P less than 0.05). During an 8-week post-discharge follow-up period three patients with a normal venogram at day 10 developed clinically apparent venous thromboembolism, which was confirmed by objective testing. All three patients belonged to the heparinoid-treated group. We conclude that 750 anti-factor Xa units Org 10172 s.c. twice daily starting preoperatively is safe and effectively reduces early deep-vein thrombosis following elective total hip replacement. Further studies on the incidence of post-discharge thromboembolism are required.

The effect of different anaesthetic techniques on the incidence of thrombosis following total hip replacement.

We performed a retrospective analysis on the influence of three types of anaesthesia on the incidence of deep vein thrombosis (DVT) following total hip replacement (THR) in consecutive patients randomized to either the low molecular weight heparinoid Org 10172 (97 patients), or placebo (99 patients). Ninety patients were operated under epidural anaesthesia, 77 patients under psoas compartment block with additional inhalation anaesthesia, and 29 patients under general anaesthesia. DVT assessment was performed by bilateral venography between days 8 and 12 postoperatively. The overall incidence of DVT in the 196 patients was 37% in the epidural anaesthesia group, 35% in the psoas compartment block group, and 36% in the general anaesthesia group. Although the incidence of DVT in patients randomized to placebo was similar in the two anaesthesia groups (53%), there was an important reduction of the occurrence of proximal DVT by the heparinoid in the psoas compartment block group (from 20 to 0%), compared to the epidural anaesthesia group (from 27 to 18%) (p less than 0.0061). Significantly more minor wound hematomas occurred in the psoas compartment block group as compared to the epidural anaesthesia group (p less than 0.05). Synergism of thrombin generation inhibition by the heparinoid and inhibition of platelet aggregation at the damaged vessel wall, by high local concentrations of bupivacaine in the psoas compartment block technique, is proposed as a possible mechanism behind this observation.

Thrombin-antithrombin III complexes in the prediction of deep vein thrombosis following total hip replacement.

In 196 consecutive patients who underwent elective total hip surgery we investigated the diagnostic accuracy of the thrombin-antithrombin III complex immunoassay, as assessed on the first, fourth and tenth postoperative day, for the development of deep vein thrombosis (DVT). Patients received either LMW-heparinoid (n = 97) or placebo (n = 99) and underwent contrast venography on the tenth postoperative day. Thrombin-antithrombin III (T-AT) plasma levels were raised in all patients on the first postoperative day and gradually decreased during the study period. T-AT plasma levels were significantly higher in patients developing DVT when compared to patients without DVT and remained so until day 10. This difference was apparent both in the LMW-heparinoid group as well as in the placebo-treated patients. ROC-curve analysis revealed no satisfactory discriminative power for the diagnosis of developing DVT at any of the studied cut-off values for T-AT. We conclude that the postoperative determination of T-AT complex plasma concentrations in hip surgery patients has no clinical utility in the prediction of postoperative DVT.