Early prediction of endocrine responsiveness in ER+/HER2-negative metastatic breast cancer (MBC): pilot study with 18F-fluoroestradiol (18F-FES) CT/PET.

BACKGROUND: 18F-fluoroestradiol (FES) positron emission tomography (PET)/computed tomography (CT) is considered an accurate diagnostic tool to determine whole-body endocrine responsiveness. In the endocrine therapy (ET)-FES trial, we evaluated 18F-FES PET/CT as a predictive tool in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients underwent an 18F-FES PET/CT at baseline. Patients with standardized uptake value (SUV) ≥ 2 received single-agent ET until progressive disease; patients with SUV < 2 were randomized to single-agent ET (arm A) or chemotherapy (ChT) (arm B). The primary objective was to compare the activity of first-line ET versus ChT in patients with 18F-FES SUV < 2. RESULTS: Overall, 147 patients were enrolled; 117 presented with 18F-FES SUV ≥ 2 and received ET; 30 patients with SUV < 2 were randomized to ET or ChT. After a median follow-up of 62.4 months, 104 patients (73.2%) had disease progression and 53 died (37.3%). Median progression-free survival (PFS) was 12.4 months [95% confidence interval (CI) 3.1-59.6 months] in patients with SUV < 2 randomized to arm A versus 23.0 months (95% CI 7.7-30.0 months) in arm B, [hazard (HR) = 0.71, 95% CI 0.3-1.7 months]; median PFS was 18.0 months (95% CI 11.2-23.1 months) in patients with SUV ≥ 2 treated with ET. Median overall survival (OS) was 28.2 months (95% CI 14.2 months-not estimable) in patients with SUV < 2 randomized to ET (arm A) versus 52.8 months (95% CI 16.2 months-not estimable) in arm B (ChT). Median OS was not reached in patients with SUV ≥ 2. 60-month OS rate was 41.6% (95% CI 10.4% to 71.1%) in arm A, 42.0% (95% CI 14.0% to 68.2%) in arm B, and 59.6% (95% CI 48.6% to 69.0%) in patients with SUV ≥ 2. In patients with SUV ≥ 2, 60-month OS rate was 72.6% if treated with aromatase inhibitors (AIs) versus 40.6% in case of fulvestrant or tamoxifen (P < 0.005). CONCLUSIONS: The ET-FES trial demonstrated that ER+/HER2- MBC patients are a heterogeneous population, with different levels of endocrine responsiveness based on 18F-FES CT/PET SUV.

Additional value of integrated 18F-choline PET/4D contrast-enhanced CT in the localization of hyperfunctioning parathyroid glands and correlation with molecular profile.

PURPOSE: The localization of hyperfunctioning parathyroid gland(s) (HPTG) in patients with primary hyperparathyroidism (PHPT) with negative or inconclusive first-line imaging is a significant challenge. This study aimed to evaluate the role of integrated 18F-choline PET/4D contrast-enhanced computed tomography (4DCeCT) in these patients, compare its detection rate and sensitivity with those of 18F-choline PET/CT and (4DCeCT), and analyse the association between choline metabolism and morphological, biochemical and molecular parameters of HPTG. METHODS: We prospectively enrolled 44 PHPT patients with negative or inconclusive first-line imaging. 18F-Choline PET/CT and 4DCeCT were performed at the same time, and integrated 18F-choline PET/4DCeCT images were obtained after coregistration. Experienced physicians examined the images. The SUVratio and degree of contrast enhancement were recorded for each positive finding. Histopathology, laboratory and multidisciplinary follow-up were used as the standard of reference. Both the detection rates and sensitivities of the three imaging modalities were calculated retrospectively. Immunohistochemistry was performed to evaluate the molecular profile of HPTGs. RESULTS: 18F-Choline PET/4DCeCT was positive in 32 of 44 patients with PHPT (detection rate 72.7%), and 31 of 31 surgically treated patients (sensitivity 100%). These results were significantly (p < 0.05) better than those of 18F-choline PET/CT (56.8% and 80%, respectively) and those of 4DCeCT (54.5 and 74%, respectively). A significant correlation between SUV and calcium level was found. In a multivariate analysis, only calcium level was significantly associated with 18F-choline PET/4DCeCT findings. SUVratio and Ki67 expression were significantly correlated. CONCLUSION: Integrated 18F-choline PET/4DCeCT should be considered as an effective tool to detect PHPT in patients with negative or inconclusive first-line imaging. Choline metabolism is correlated with both calcium level and Ki67 expression in HPTG.

Approval rating and opinion of outpatients and general practitioners toward generic drugs: a questionnaire-based real-world study.

PURPOSE: Generic drugs use in the Liguria region is higher than the Italian average, but lower than in other European countries. No data exist about real-life prescription and level of awareness of generic drugs. In this study, we analyzed demographic, social, economic and cultural factors that may affect the level of awareness of generic drugs and their effective use. METHODS: We conducted a population survey using a structured questionnaire, administered to a sample of 8 outpatient clinics of general practitioners located in different districts of Genoa (Liguria, Italy). Multivariate logistic modeling was adopted to study the relationship between awareness/use of generic drugs and characteristics of subjects. RESULTS: Out of 2,000 outpatients surveyed, 95% were aware of generic drugs: these were mostly females (OR =2.2, 95% CI: 1.4-3.6), >35 years old (OR >6.0 vs 18-35 years), with a high level of education (OR >4.4 vs "elementary sch"), living in the west side of the city (OR =1.9 vs center); of these, only 59% declared that they effectively use generic drugs. Users were younger (OR =3.1, 18-35 years vs >65 years), with a high level of education (high school/university degree vs no title/elementary/secondary school OR =1.7), and were aware of the lower cost compared with branded drugs, and were mainly informed by pharmacists and physicians. CONCLUSIONS: Although subjects were substantially aware of the existence of generic drugs, ~40% still did not use them; doubts about their efficacy seem to be mainly driven by the idea that cheaper drugs lead to lower product quality, in terms of efficacy, safety and tolerability. New education policies on generic drugs are needed.

Thyroid nodules with indeterminate cytology: prospective comparison between 18F-FDG-PET/CT, multiparametric neck ultrasonography, 99mTc-MIBI scintigraphy and histology.

PURPOSE: To evaluate the role of (18)F-flurodeoxiglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) in predicting malignancy of thyroid nodules with indeterminate cytology. PATIENTS AND METHODS: We analysed 87 patients who have been scheduled to undergo surgery for thyroid nodule with indeterminate cytology. All patients underwent (18)F-FDG-PET/CT, multiparametric neck ultrasonography (MPUS), and (99m)Tc-methoxyisobutylisonitrile scintigraphy ((99m)Tc-MIBI-scan). Histopathology was the standard of reference. We compared the sensitivity (SE), specificity (SP), accuracy (AC), positive (PPV) and negative predictive (NPV) values of (18)F-FDG-PET/CT with those of (99m)Tc-MIBI-scan and MPUS in detecting cancer. Univariate and multivariate analyses evaluated the association between each diagnostic tool and histopathology. RESULTS: On histopathology, 69 out of 87 nodules were found to be benign and 18 to be malignant. The SE, SP, AC, PPV and NPV of (18)F-FDG-PET/CT were 94, 58, 66, 37 and 98% respectively. The SE, AC and NPV of (18)F-FDG-PET/CT were significantly higher than those of MPUS and (99m)Tc-MIBI-scan. The association of both positive (18)F-FDG-PET/CT and MPUS (FDG+/MPUS+) showed significantly lower SE (61% vs 94%) and NPV (88% vs 98%) than (18)F-FDG-PET/CT alone, but significantly higher SP (77% vs 58%). On univariate analysis, (18)F-FDG-PET/CT and the combination of FDG+/MPUS+ and of FDG+/MIBI- were all significantly associated with histopathology. On multivariate analysis, only FDG+/MIBI- was significantly associated with histopathology. CONCLUSION: The AC of (18)F-FDG-PET /CT in detecting thyroid malignancy is higher than that of (99m)Tc-MIBI-scan and MPUS. A negative (18)F-FDG-PET/CT correctly predicts benign findings on histopathology. The association of FDG+/MPS+ is significantly more specific than (18)F-FDG-PET/CT alone in identifying differentiated thyroid cancer. A positive (18)F-FDG-PET/CT is significantly associated with malignancy when qualitative (99m)Tc-MIBI-scan is rated as negative.

PIK3CA Mutation, Aspirin Use after Diagnosis and Survival of Colorectal Cancer. A Systematic Review and Meta-analysis of Epidemiological Studies.

AIMS: Regular aspirin use has been associated with inhibition of the whole spectrum of colorectal carcinogenesis, including prevention of metastases and reduced total mortality in colorectal cancer. Preclinical data show that aspirin down-regulates PI3 kinase (PI3K) signalling activity through cyclo-oxygenase-2 (COX-2) inhibition, leading to the hypothesis that the effect of aspirin might be different according to PIK3CA mutational status, but epidemiological studies have led to conflicting results. The aim of this study was to assess the relationship between PIK3CA status and the efficacy of regular use of aspirin after diagnosis on overall survival in colorectal cancer patients. MATERIALS AND METHODS: We identified studies that compared post-diagnosis aspirin efficacy in colorectal cancer patients identified by PIK3CA status. Hazard ratios for overall survival were meta-analysed according to PIK3CA status by inverse variance weighting. A pooled test for treatment by PIK3CA status interaction was carried out by weighted linear meta-regression. All statistical tests were two-sided. RESULTS: The overall effect of aspirin was not significant (summary risk estimate = 0.82; 95% confidence interval 0.63-1.08, P = 0.16; I(2) = 57%). In PIK3CA mutant disease (n = 588), aspirin use reduced total mortality by 29% (summary risk estimate = 0.71; 95% confidence interval 0.51-0.99, P = 0.04; I(2) = 0%), whereas in PIK3CA wild-type disease (n = 4001), aspirin use did not reduce overall mortality (summary risk estimate = 0.93; 95% confidence interval 0.61-1.40; P = 0.7; I(2) = 80%) (P interaction = 0.39). There was a beneficial trend for aspirin on cancer-specific survival in PI3KCA mutated subjects (summary risk estimate = 0.37, 95% confidence interval 0.11-1.32, P = 0.1), albeit with high heterogeneity (Q chi-squared = 3.41, P = 0.07, I(2) = 70.7%). CONCLUSION: These findings suggest that the benefit of post-diagnosis aspirin treatment on overall mortality in colorectal cancer may be more marked in PIK3CA mutated tumours, although the low number of studies prevents definitive conclusions. Trials addressing this issue are warranted to assess the efficacy of aspirin in the adjuvant setting.

18F-FDG PET/CT is a prognostic biomarker in patients affected by bone metastases from breast cancer in comparison with 18F-NaF PET/CT.

AIM: To compare 18F-FDG PET/CT and 18F-NaF PET/CT with respect to disease prognostication and outcome in patients affected by bone metastases from breast cancer (BC). PATIENTS, METHODS: We retrospectively investigated 32 women with BC and documented bone metastases. Semi-quantitative parameters were applied to 18F-FDG PET/CT and 18F-Na PET/CT in order to evaluate disease extent and tumour metabolism. We used time-to-event analyses (Kaplan Meier and COX proportional hazard methods) to estimate progression-free (PFS) and overall survival (OS) in order to assess the independent prognostic value of 18F-FDG PET/CT and 18F-Na PET/CT. RESULTS: The sensitivity of 18F-NaF PET/CT (100%) was higher (p < 0.05) than that of 18F-FDG PET/CT (72% and 72%). None of the 18F-FDG PET/CT-negative patients showed disease progression at the end of follow-up. After adjustment for age, Ki-67 levels, presence of visceral metastases, hormone therapy, duration of bone disease and response to first-line therapy, only 18F-FDG SUV mean [HR 15.7, 95% confidence interval (CI) 1.15-214.5] and 18F-FDG whole-body bone metabolic burden (WB-B-MB) (HR 16.9; 95%CI 1.87-152.2) were independently and significantly associated with OS. None of the 18F-NaF PET/CT parameters were associated with OS. None of the conventional clinical prognostic parameters remained significantly associated with OS after the inclusion of PET/CT parameters in the model. CONCLUSION: 18F-FDG PET/CT is independently associated with OS in BC patients with bone metastases and its prognostic impact seems to be higher than conventional clinical and biological prognostic factors. Although 18F-NaF PET/CT has a higher diagnostic sensitivity than 18F-FDG PET/CT, it is not independently associated with OS.

Modulation of lipid homeostasis in response to continuous or intermittent high-fat diet in pigs.

A high-fat diet is known to induce atherosclerosis in animal models. Dietary factors and timing of atherogenic food delivery may affect plasma lipoprotein content composition and its potential atherogenic effect. Increasingly often, humans spend periods/days eating in a completely unregulated way, ingesting excessive amounts of food rich in oils and fats, alternating with periods/days when food intake is more or less correct. We investigate the effect on lipid homeostasis of a high-fat diet administered either continuously or intermittently. We investigated control pigs receiving standard diet (C, n=7), pigs receiving a high-fat diet every day for 10 weeks (CHF, n=5), and pigs receiving a high-fat diet every other week for 10 weeks (IHF, n=7). IHF animals were shown to have a different lipid profile compared with CHF animals, with a significant increase in high-density lipoproteins (HDL) levels with respect to C and CHF groups. CHF also showed significantly higher values of TC/HDL cholesterol compared with C and IHF. Hepatic expression analysis of genes involved in lipid homeostasis showed an increasing trend of nuclear receptor LXRα along with its target genes in the CHF group and in the IHF group, whereas SREBP2 and LDLr were significantly inhibited. A significant correlation was found between ABCA1 expression and circulating levels of HDL-C. Periodic withdrawals of a high-fat atherogenic diet compared with a regular administration results in a different adaptive response of lipoprotein metabolism, which leads to a significantly higher plasma level of HDL-C and lower TC/HDL-C.

The effect of metformin on apoptosis in a breast cancer presurgical trial.

BACKGROUND: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial. METHODS: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery. RESULTS: Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1). CONCLUSION: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.

Clinical and epidemiological comparison of patients affected by palmoplantar plaque psoriasis and palmoplantar pustulosis: a case series study.

BACKGROUND: In 2007 the International Psoriasis Council proposed that palmoplantar pustulosis (PPP) should be considered a separate condition from psoriasis, despite the presence of certain phenotypes common in both diseases. OBJECTIVES: To describe and compare demographic and clinical characteristics among patients with PPP and palmoplantar plaque psoriasis. METHODS: This was a retrospective case series study from 2005 to 2010. The following data were obtained: age, sex, family history, smoking habits, nail involvement, joint involvement, disease duration, lesion morphology (plaque or pustular), histological diagnosis, comorbidities, and Physician's Global Assessment (PGA) score for extrapalmoplantar lesions. The sample size calculation indicated that 80 patients, 40 patients for each group (palmoplantar plaque psoriasis and PPP) were needed to see clinically relevant differences between groups. RESULTS: Ninety patients were selected, 51 with palmoplantar plaque psoriasis and 39 with PPP. No statistically significant differences were registered between patients affected by PPP and palmoplantar plaque psoriasis as regards age at onset of the disease (48 vs. 44 years; P=0·4), disease duration (6 vs. 10 years; P=0·1), family history of psoriasis (28% vs. 33%; P=0·7), concomitant arthritis (26% vs. 25%; P=1·0), or smoking habits (54% vs. 41%; P=0·2). We observed a female predominance (P=0·01) and a lesser frequency of nail involvement (P=0·03) in patients affected by PPP. CONCLUSIONS: Our data suggest a close relationship between PPP and psoriasis. The existing data concerning epidemiology, clinical presentation, genetics, histopathology and pathogenesis do not permit a clear distinction between these two entities, which seem to coincide in many aspects. PPP appears to have a marked predilection among female smokers.

Role of low-cost thyroid follow-up in children treated with radiotherapy for primary tumors at high risk of developing a second thyroid tumor.

AIM: Differentiated thyroid cancer (DTC) is uncommon in childhood and data on its prevalence as a second malignant neoplasm (SNM) after radiotherapy (RT) for malignancies are limited. We evaluated: 1) the incidence DTC in pediatric-oncologic patients treated with RT; 2) the relationship between DTC, RT and the features of the first malignancy; 3) the usefulness of thyroid follow-up in irradiated oncological patients. METHODS: We have followed up 252 patients treated with RT out of 966 oncologic pediatric patients. Thyroid follow-up included TSH level evaluation and neck ultrasonography. In the presence of thyroid nodule/s ≥1 cm and/or with ultrasonography suspicious for malignancy, fine needle aspiration biopsy (FNAB) was performed. When papillary/follicular lesions were detected by cytology, thyroidectomy was performed. If DTC was confirmed, patients underwent radioactive iodine (RAI) treatment. RESULTS: At least one thyroid nodule was detected in 106 irradiated patients (42%): 45 patients underwent FNAB and 27 underwent thyroidectomy. Seventeen DTC (6.7%) were found on histology. A higher incidence of DTC was seen in patients with neuroblastoma (38%) or Wilms' tumor (18%). One third of DTC showed capsule invasion, and one fourth node involvement. Eleven patients, treated with a single RAI treatment, showed undetectable thyroglobulin levels after rh-TSH-stimulation. Five patients underwent at least two RAI treatments: four patients showed complete remission and one patient partial remission. CONCLUSION: A high rate of DTC, often with invasive features, was observed in children treated with RT for primary tumors. This finding underlines the usefulness of thorough low-cost thyroid follow-up in this high-risk population.

Cellular cholesterol efflux and cholesterol loading capacity of serum: effects of LDL-apheresis.

High LDL-cholesterol (LDL-C) characterizes familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH). LDL-apheresis, used in these patients to reduce LDL-C levels, has been shown to also affect HDL levels and composition. We studied LDL-apheresis effects on six FH and nine FCH subjects' serum capacity to modulate cellular cholesterol efflux, an index of HDL functionality, and to load macrophages with cholesterol. Serum cholesterol efflux capacity (CEC) and macrophage cholesterol loading capacity (CLC) were measured before, immediately after, and two days after LDL-apheresis. The procedure reduced total cholesterol (TC), LDL-C, and apoB plasma levels (-69%, -80% and -74%, respectively), parameters only partially restored two days later. HDL-C and apoA-I plasma levels, reduced after LDL-apheresis (-27% and -16%, respectively), were restored to almost normal levels two days later. LDL-apheresis reduced serum aqueous diffusion (AD) CEC, SR-BI-CEC, and ABCA1-CEC. AD and SR-BI were fully restored whereas ABCA1-CEC remained low two days later. Sera immediately and two days after LDL-apheresis had a lower CLC than pre-LDL-apheresis sera. In conclusion, LDL-apheresis transiently reduces HDL-C levels and serum CEC, but it also reduces also serum capacity to deliver cholesterol to macrophages. Despite a potentially negative effect on HDL levels and composition, LDL-apheresis may counteract foam cells formation.

Clinical trials with retinoids for breast cancer chemoprevention.

Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGF-binding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.

Upregulation of the immune system in primary hypercholesterolaemia: effect of atorvastatin therapy.

OBJECTIVES: High levels of plasma high sensitivity C-reactive protein (CRP), sensitive to therapy with statins, have been described in hypercholesterolaemia. In vitro evidence shows that CRP activates the complement system, which, in turn, leads to an increased expression of ICAM-1. Our objectives were to verify whether primary hypercholesterolaemia (PHC) is associated with an upregulation of the inflammatory/immune response, and whether this is sensitive to atorvastatin. METHODS AND RESULTS: We examined the levels of sICAM-1, C3, C4 complement fractions in 48 patients with PHC, with (CAD group) or without (No-CAD group) coronary artery disease (CAD) in comparison with a group of 48 healthy controls. The two patient groups were studied before and after atorvastatin therapy. Both hypercholesterolaemic groups showed higher mean values of sICAM-1, C3 and C4 (P < 0.0001) when compared with the controls. The two groups of patients responded differently to atorvastatin therapy. After 3 months, the C3 levels normalized in both groups of patients (P < 0.02 compared with basal values); C4 was greatly reduced only in the CAD group (P < 0.01). After 12 months of therapy, in CAD group C3 mean levels were still significantly lower than baseline values (P < 0.01); a further decrease in the C4 values (P < 0.05 with respect to levels after 3 months of therapy) and also a substantial reduction in sICAM-1 values (P < 0.001 with respect to basal values) were observed. CONCLUSIONS: High plasma values of C3 and C4 in PHC cluster with high values of sICAM-1, distinguish subjects with CAD and could be used to monitor the anti-inflammatory effect of statin therapy in these patients.

Up regulation of C3, C4, and soluble intercellular adhesion molecule-1 co-expresses with high sensitivity C reactive protein in familial hypoalphalipoproteinaemia: further evidence of inflammatory activation.

OBJECTIVE: To test the working hypothesis that inflammation underlying precocious and severe coronary atherosclerotic disease in familial hypoalphalipoproteinaemia (FH) can be mediated by up regulation of the innate immune response. METHODS AND RESULTS: 52 patients with FH were compared with 52 healthy controls with regard to immune system markers such as C reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), C3c, and C4. Patients differed from controls in their significantly lower concentrations of high density lipoprotein cholesterol (30.2 (4.0) v 50.5 (13.6) mg/dl, p < 0.0001) and apolipoprotein A I (113.2 (19.9) v 148.7 (25.1) mg/dl, p < 0.0001) and their higher triglyceride (139.3 (63.2) v 81.4 (41.7) mg/dl, p < 0.0001) and CRP plasma concentrations (median 0.33 mg/dl, range 0.02-4.66 mg/dl v median 0.07 mg/dl, range 0.02-0.85 mg/dl, p < 0.0001), but not in their total cholesterol and low density lipoprotein cholesterol concentrations. Concentrations of protein complement were higher in patients (C3: 150.8 (42.3) v 101.9 (17.4) mg/dl, p < 0.0001; C4: 35.5 (13.6) v 22.8 (6.4) mg/dl, p < 0.0001) and sICAM-1 concentrations were more than double those found in the controls (335.1 (107.5) v 159.5 (78.2) mg/dl, p < 0.0001). CONCLUSIONS: Increased concentrations of sICAM-1, C3c, and C4 co-express with high concentrations of CRP in FH. The lack of signs and symptoms of inflammation in these patients may suggest that the immune response is up regulated as part of the pro-inflammatory mechanisms that are activated in this atherogenic condition.