Bevacizumab-associated hyperlipoproteinemia type IIb in a patient with advanced invasive-ductal breast cancer.

AIM: We report a case of bevacizumab-associated hyperlipoproteinemia in a patient with advanced breast cancer. CASE SUMMARY: A 57-year-old woman with advanced invasive-ductal breast cancer was administered bevacizumab from March 2008 to February 2009. Pretreatment laboratory showed borderline hypercholesterolemia (5.1 mmol/L, 197 mg/dL) and normal triglycerides (1.3 mmol/L, 115 mg/dL). Three months on treatment with bevacizumab, both serum cholesterol (11.9 mmol/L, 460 mg/dL) and triglycerides (7.4 mmol/L, 655 mg/dL) increased substantially, and remained well above the normal range for a period of bevacizumab treatment. From March 2008 to August 2008, the patient also received anticancer treatment with liposomal doxorubicin that was stopped early due to hand-foot syndrome. No concurrent hyperlipidemic drugs have been taken by the patient at the time of bevacizumab treatment. In February 2009, bevacizumab was stopped and the patient went on to receive paclitaxel for hepatic tumor progression. By December 2009, both serum triglycerides (1.3 mmol/L, 115 mg/dL) and cholesterol (3.2 mmol/L, 123 mg/dL) had normalized. DISCUSSION: This is the first published case of bevacizumab-associated hyperlipoproteinemia. By applying the Naranjo ADR probability scales, at least a possible relationship between hyperlipoproteinemia type IIb and bevacizumab in this patient is supported by the data (Naranjo score 4). No hyperlipidemic drugs were given concurrently with bevacizumab, and the serum cholesterol and triglycerides decreased quickly after bevacizumab was discontinued. CONCLUSIONS: This study describes a case of bevacizumab-associated hyperlipidemia. Patients receiving bevacizumab should have their cholesterol and triglycerides checked for potential worsening.

Procollagen type I N-propeptide is a predictor of skeletal morbidity in patients with malignant osteolytic bone disease on bisphosphonates.

BACKGROUND: There is an urgent need for individualized treatment of malignant bone disease (MBD), as the clinical benefit from bone-targeted therapies is moderate. We assessed the predictive value of the bone formation marker procollagen type I N-propeptide (PINP) for skeletal morbidity in patients with MBD receiving pamidronate. METHODS: Seventy patients with advanced MBD were randomized to receive pamidronate 60 mg (n = 35) or 90 mg (n = 35) every 3 weeks for six cycles in a double-blind study. PINP was analyzed at baseline and before each administration of pamidronate, using a validated ELISA. Serum PINP concentrations were compared with pain response (visual analog scale VAS, composite pain score) and skeletal morbidity (skeletal-related events, SRE) using Student's T-test, Wilcoxon rank-sum and log-rank test, respectively. RESULTS: Patients with ≥20% pain reduction in the VAS had lower baseline PINP concentrations when compared to patients with <20% VAS response (P < 0.0001). A high baseline serum PINP concentration (highest tertile versus lower two tertiles) was significantly associated with a shorter duration of pain response (P < 0.0001) and a shorter time interval to first SRE (P < 0.008). Sensitivity of a low baseline PINP serum concentration for freedom from SRE at 1 year from randomization was 75% (15 out of 20 patients), while specificity was 82% (27 out of 33 patients). CONCLUSIONS: Serum PINP has been shown to be a significant predictor for skeletal morbidity in patients with MBD on pamidronate treatment. Prospective validation of PINP in patients with MBD to assess the prognosis or individualize bone-targeted treatment is justified.

[Update of lipid lowering therapy]. / Update der lipidsenkenden Therapie.

Dyslipidemia is one of the most important cardiovascular risk factors. Accordingly preventive measures to normalize lipids are of great importance. The indication for a lipid lowering therapy according to current guidelines focuses on the identification of a patient's global risk, i.e. the contribution of all major cardiovascular risk factors. The selection of the lipid lowering therapy should be appropriate for the kind of lipid disorder. This may be a special challenge with respect to target values and safety aspects. Statins in monotherapy are generally considered safe drugs. Higher dosages may be associated with liver toxicity and muscle problems. Lifestyle management should underpin all lipid management strategies.

Hypertriglyceridemia as a possible risk factor for prostate cancer.

We retrospectively studied anthropometric and laboratory parameters (including serum triglycerides, cholesterol), as well as comedication in 504 patients diagnosed with prostate cancer between January 1997 and August 2002 at a single referral center, and compared these patients with 565 age-matched patients with benign prostatic hyperplasia. A positive correlation was found between serum triglycerides and prostate cancer (odds ratio: 1.148/mmol/l; 95% confidence interval (CI) 1.003-1.315; P<0.05) after correcting for age, body mass index, diabetes and comedication with statins. Hypertriglyceridemia may increase the risk of prostate cancer, and the prognostic relevancy of serum triglycerides should be studied prospectively.

Short-term effects of atorvastatin on C-reactive protein.

AIM: To study the short-term effect of atorvastatin on C-reactive protein (CRP) in patients with or at risk for coronary heart disease. METHODS AND RESULTS: One hundred and fifty-five randomly selected patients from the SWiss Intervention Trial for lowering CHolesterol (SWITCH) were assessed for high sensitivity CRP, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides at baseline, and after 1 and 3 months of treatment with atorvastatin at various doses to reach pre-defined lipid target values. The median decrease of cholesterol was 28% after 1 month and 35% after 3 months. LDL-cholesterol was decreased by 37% and 45%, HDL-cholesterol was increased by 7% and 8%, respectively. Patients with a low CRP baseline concentration (lowest quartile <1.34 mg. l(-1)) displayed no significant change, whereas patients in the other quartiles showed a significant decrease, of 22% to 40% (P -value <0.05 to <0.001) at 1 month and of 32% to 36% after 3 months compared to baseline. The decrease in CRP lowering was thus fully established by 1 month and this response was independent of lipid and lipoprotein changes as well as atorvastatin doses. CONCLUSION: Atorvastatin significantly decreases CRP concentrations after 4 weeks of therapy. These results may be important with respect to the early benefit of statin therapy.

Comparability of serum and plasma concentrations of haemostasis activation markers.

Since serum and plasma D-dimer concentrations correlate very well, we evaluated the comparability of other haemostasis activation markers in plasma and serum. Prothrombin fragment F1+2, fibrin monomer and D-dimer concentrations were measured with commercially available immunoassays in serum and plasma. Serum to plasma ratios were evaluated to determine the direct (prothrombin fragment F1+2) and indirect (fibrin monomer, D-dimer) downstream influence of prothrombinase on the serum to plasma comparability. Prothrombin fragment F1+2 serum and plasma concentrations did not correlate (R2 = 0.09, ns), while an unexpected high degree of correlation was found for fibrin monomer (R2 = 0.66, p < 0.001), and, as expected, a very good correlation was found for D-dimer (R2 = 0.94, p < 0.001). Median serum to plasma ratios decreased from prothrombin fragment F1+2 (16.26) to fibrin monomer (2.24, p < 0.001) and D-dimer (1.00, p < 0.001), following a highly linear relationship (R2 = 0.93) Plasma and serum concentrations of the evaluated markers correlate the better the farther from prothrombinase activity the respective marker is generated. Serum is not suitable for prothrombin fragment F1+2 measurements, whereas fibrin monomer serum concentrations seem of value for research applications. With the used assay, serum seems an appropriate matrix for clinical D-dimer measurements. This would considerably simplify testing strategies. Validation in further clinical trials is needed.

Acid-base and endocrine effects of aldosterone and angiotensin II inhibition in metabolic acidosis in human patients.

Chronic metabolic acidosis (CMA) in human beings is characterized by increased renin-angiotensin-aldosterone (RAA) activity and cortisol secretion as well as nitrogen wasting. The purpose of this study was to examine whether and to what extent increased RAA activity (i.e., angiotensin II or aldosterone) regulates acid-base equilibrium in CMA and thus might co-determine the severity of acidosis. CMA was induced in 8 normal subjects by oral NH4Cl administration (2.1 mmol/kg body weight per day) for 7 days, followed by a 7-day period of spironolactone (100 mg, 4 times a day by mouth), followed by a 4-day period of spironolactone and losartan (100 mg, every day by mouth). NH4Cl feeding was continued during all study periods. Spironolactone resulted in exacerbation of acidosis ((HCO3)p decreased from 19.8+/-0.4 mmol/L to 17.7+/-0.6 mmol/L, P<.005) because of a large increase in endogenous acid production, as evidenced by significant increases in net acid excretion (116 to 185 mmol/day, P<.005), urinary anion gap (+31 mEq/day, P<.05), and sulfate excretion (+32 mEq/day, P<.05). Plasma potassium increased from 4.2 to 4.6 mmol/L (P<.05) because of decreased urinary potassium excretion (from 108 to 92 mmol/day, P<.05). Plasma angiotensin II, cortisol, aldosterone, urinary aldosterone, urinary tetrahydrocortisol, free cortisol, and nitrogen excretion increased significantly. The subsequent addition of losartan to spironolactone administration resulted in further exacerbation of acidosis ((HCO3)p decreased to 15.7+/-0.4 mmol/L, P<.05) and hyperkalemia (5.0 mmol/L, P<.05) with no change in plasma anion gap. Renal potassium excretion decreased from 92 to 73 mmol/day (P<.05) on day 1. Exacerbation of acidosis was accounted for by a renal mechanism, as evidenced by the significant decrease in net acid excretion and unchanged urinary unmeasured anion and nitrogen excretion. We conclude the following: (1) AT-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect. Angiotensin II is an important modulator of the renal acid excretory response to CMA in human beings. (2) Inhibition of aldosterone action by spironolactone in CMA results in an increase in endogenous acid production and exacerbates acidosis by a non-renal mechanism that is mediated, at least in part, by exacerbated hyperglucocorticoidism.

Biochemical markers of bone turnover in patients with thyroid dysfunctions and in euthyroid controls: a cross-sectional study.

Hyperthyroidism is associated with reduced bone mineral density. Conflicting data exist regarding the effects of thyroxine therapy on bone metabolism. The aim of the present study was to assess changes in markers of bone turnover in thyroid dysfunction. A total of 28 patients with overt hyperthyroidism, eight patients with suppressed TSH levels (thyroid hormones within the euthyroid range, no T4 therapy), 25 euthyroid and four hypothyroid patients were included in the present study. Hyperthyroidism resulted in increased bone metabolism, as reflected by increased bone resorption and bone formation parameters. No significant differences in mean levels between patients with TSH supression and those with euthyroidism could be observed; however, a higher frequency of elevated urinary PYD- and DPD excretion rates were noted in patients with TSH suppression. Regression analysis revealed highly significant correlations between bone resorption markers and thyroid parameters, suggesting, that even a mild thyroid hormone excess may lead to an increase in bone resorption. In subjects with suppressed TSH levels and peripheral thyroid hormone levels within the euthyroid range, elevated bone resorption markers point to subclinical hyperthyroidism, if other reasons for an increase in bone turnover rates can be excluded.

Effect of thyroid hormones on Lp(a) and lipid metabolism.

The effect of thyroid hormones on lipoprotein(a) plasma concentrations and the other parameters of lipoprotein metabolism was studied in 158 patients with thyroid dysfunction and in 37 euthyroid controls (cross-sectional study). Multiple regression analysis revealed that 65.5% of the variability in lipoprotein(a) levels were predicted by changes in lipoprotein(a) phenotypes (60.5%), thyrotropin (3.5%), and age (0.8%). The lipid parameters, however, showed no significant effect on lipoprotein(a). A subgroup analysis on samples from patients with large lipoprotein(a) isoforms showed that 28% of the variability in lipoprotein(a) concentrations could be explained by changes in thyroid function (19.1%), age (6.5%) and triglycerides (3.5%). Much stronger correlations were found between thyrotropin and total cholesterol, low density lipoprotein cholesterol or apolipoprotein B respectively (R2=0.951 for low density lipoprotein cholesterol, R2=0.801 for apolipoprotein B). Our data suggest that thyroid hormone is a significant modulator of lipoprotein(a) metabolism. However, different mechanisms are responsible for the change in lipoprotein(a) levels and for the decrease in total- and low density lipoprotein cholesterol levels.

Diagnostic and prognostic value of biochemical markers in malignant bone disease: a prospective study on the effect of bisphosphonate on pain intensity and progression of malignant bone disease.

Seventy cancer patients with malignant osteolytic bone disease received pamidronate every three weeks for a maximum of six cycles. Bone resorption parameters, urinary calcium excretion, and pain parameters were assessed at baseline and throughout the study. At baseline, 80-95% of patients showed elevated urinary pyridinoline, deoxypyridinoline, Osteomark NTx and serum ICTP levels, whereas only 35% of patients had elevated urinary CrossLaps excretion rates. During bisphosphonate therapy, significant decreases in Osteomark NTx, CrossLaps and calcium excretion were observed, which were not related to the clinical outcome. The baseline levels of bone resorption markers were used to predict the probability of non-progressive bone disease or reduction in pain intensity during bisphosphonate therapy. Significant predictors of non-progressive bone disease were urinary pyridinoline and serum ICTP levels; significant predictors of reduction in pain intensity were urinary free deoxypyridinoline and serum ICTP levels. Our data indicate that serum ICTP levels predict significantly the response to bisphosphonate therapy in patients with advanced malignant osteolytic bone disease. CrossLaps did not predict the clinical outcome, but decreased significantly during bisphosphonate therapy. Our data demonstrate that the different bone resorption markers are reflecting different aspects of bone metabolism, and therefore differ in their diagnostic and prognostic properties.

Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM.

Fibrates and HMG CoA reductase inhibitors are commonly used in the treatment of diabetic dyslipidaemia. However, these two groups of drugs have not been compared in diabetic patients in a randomized controlled trial. Therefore, a multicentre study was performed in 73 subjects with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and combined hyperlipidaemia (serum cholesterol 6.2-10.0 mmol l(-1), serum triglycerides 2.3-10.0 mmol l(-1)), comparing the efficacy of 400 mg bezafibrate with 10 mg simvastatin in a double-blind fashion. Treatment with bezafibrate during 12 weeks reduced serum triglycerides significantly more than simvastatin (-41% vs -22%, p < 0.001) and increased HDL cholesterol more (bezafibrate: + 17% vs simvastatin: + 9%, p < 0.05). LDL cholesterol levels decreased by 14% (p < 0.001) during simvastatin and increased by 21% (p < 0.01) during bezafibrate. This increase in LDL cholesterol was positively correlated with fasting serum triglycerides (p < 0.001) and was associated with a reduction of the serum apolipoprotein B concentration, suggesting an increase in LDL particle size. Metabolic control of diabetes (fasting glycaemia; HbA1c) and insulin secretion (C-peptide levels) were unaffected by both treatments. The incidence of side-effects during treatment was similar for both drugs. Thus, 400 mg bezafibrate mainly increases HDL cholesterol and lowers serum triglycerides but at the expense of an increase in LDL cholesterol; 10 mg simvastatin lowers LDL cholesterin more effectively but has a smaller effect on HDL cholesterol and triglycerides.

[Lipoprotein(a) and hemostasis activation markers in angina pectoris]. / Lipoprotein(a) und Hämostase-Aktivierungsmarker bei Angina pectoris.

STATEMENT OF PROBLEM: To analyse whether lipoprotein(a) is a risk factor for myocardial infarction, stroke and acute peripheral arterial occlusion in coronary heart disease and whether this risk can be assessed by clotting activation markers. PATIENTS AND METHODS: A partly prospective, partly retrospective study of data on 237 consecutive patients (201 men, 36 women; mean age 55 [24-76] years) who had undergone coronary arteriography because of severe angina. Concentrations were measured for: beta-thromboglobulin, platelet factor 4, fibrinopeptide A, D-dimers, thrombin-antithrombin III factor (TAT), prothrombin fragments 1 + 2, lipoprotein(a), apolipoprotein A-I (apoA-I), cholesterol and triglycerides. Analysis of any relationship between the findings on coronary arteriography (degree of stenosis) and the occurrence of myocardial infarction, stroke and acute peripheral arterial occlusion before and during the 2 years after the arteriography. RESULTS: There was no correlation between lipid parameters and clotting or platelet activation markers. Patients with a history of acute peripheral arterial occlusion had raised values for lipoprotein(a) and TAT. In the prospective part of the study (i.e. during the first 2 years after blood samples had been taken), there was no correlation. CONCLUSIONS: In patients with coronary artery disease and angina pectoris no correlation was found between lipoprotein(a) and haemostasis activation markers. None of these parameters--prospectively evaluated--could predict risk of thromboembolism.

[Tumor-induced anemia and markers of inflammation]. / Tumoranämie und Entzündungsmarker.

Anemia of cancer patients is multifactorial but often resembles anemia of chronic inflammatory disorders. We investigated the possibility of measurably increased parameters of inflammation in the serum of cancer patients and examined the correlation of hemoglobin levels, serum iron, and markers of inflammatory response in 201 cancer patients. Serum levels of CRP, ferritin, s-IL-2R, neopterin levels and TNF were assayed with ELISA tests. Statistically significant correlations were found between hemoglobin levels, CRP (Pearson's R = -0.451; p < 0.0001), serum iron (R = 0.326) and ferritin levels (R = -0.449). No significant correlations were seen between hemoglobin levels and neopterin or s-IL-2R. The correlation between hemoglobin levels in cancer patients and elevated markers of inflammatory responses, such as CRP, suggest that cytokines involved in the inflammatory responses may be at least partially responsible, directly or indirectly, for anemia in cancer patients.

Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A.

Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an i.v. bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 x 150 micrograms rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1-5) in the two patients were 9.6 +/- 1.3 and 9.2 +/- 1.2 mmol/l, respectively, and fell to 4.4 +/- 0.4 and 5.1 +/- 0.5 mmol/l on treatment days 8-10. Fasting insulin (2950 +/- 450 and 690 +/- 125 pmol/l), C-peptide (2217 +/- 183 and 1317 +/- 235 pmol/l) and proinsulin control levels (125 +/- 35 and 66 +/- 0 pmol/l) also decreased by approximately 65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent.