Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

Severe vitamin D deficiency is associated with frequently observed diseases in medical inpatients.

INTRODUCTION: Vitamin D deficiency consequences may go beyond altered calcium homeostasis and musculoskeletal disease. Medical inpatients are often vitamin D-deficient, but little information is available about the relation of vitamin D status with extra-skeletal disorders in this population. METHODS: We analysed the relationship between the concentrations of 25-hydroxyvitamin D [25(OH)D], the marker of vitamin D status, and the conditions most commonly causing admission in 115 consecutive medical inpatients. RESULTS: Sixty-five subjects (56.5%) had severe vitamin D deficiency [25(OH)D < 8 ng/ml]. Age (ß = -0.35, p = 0.01) and hepatic disease (ß = -0.21, p = 0.02) were significant correlates of 25(OH)D levels. Compared with patients with ≥ 8 ng/ml 25(OH)D, those with < 8 ng/ml 25(OH)D had significantly higher parathyroid hormone (PTH) concentrations [123 (92.7-208.2) ng/l vs. 88 (68.5-129.5) ng/l, p < 0.001], were significantly more likely to have arterial hypertension (OR 2.76, 95% CI 1.16-6.58), heart failure (HF) (OR 2.49, 95% CI 1.14-5.47), cerebrovascular disease (OR 3.23, 95% CI 1.41-7.39), and infections (OR 2.44, 95% CI 1.02-5.87), and stayed in hospital significantly longer (10 days vs. 7.5 days, p = 0.01). Only the probability of having an infection remained significantly higher in cases with severe vitamin D deficiency after adjustment for age (OR 2.41, 95% CI 1.03-5.68) and persisted after further correcting for presence of hepatic disease and PTH values (OR 2.66, 95% CI 1.03-6.88). A significant association between PTH and HF (OR 2.32, 95% CI 1.05-5.09) and length of hospitalisation (ß = 0.22, p = 0.04) emerged in the fully adjusted regression models. CONCLUSIONS: Severe vitamin D deficiency is associated with commonly presenting extra-skeletal diseases in medical inpatients. With the exception of infections, this association is mainly driven by age. Additional studies are needed to determine whether vitamin D testing on admission may help stratifying specific categories of patients by clinical severity.

Pericardial effusion in oncological patients: current knowledge and principles of management.

BACKGROUND: This article provides an up-to-date overview of pericardial effusion in oncological practice and a guidance on its management. Furthermore, it addresses the question of when malignancy should be suspected in case of newly diagnosed pericardial effusion. MAIN BODY: Cancer-related pericardial effusion is commonly the result of localization of lung and breast cancer, melanoma, or lymphoma to the pericardium via direct invasion, lymphatic dissemination, or hematogenous spread. Several cancer therapies may also cause pericardial effusion, most often during or shortly after administration. Pericardial effusion following radiation therapy may instead develop after years. Other diseases, such as infections, and, rarely, primary tumors of the pericardium complete the spectrum of the possible etiologies of pericardial effusion in oncological patients. The diagnosis of cancer-related pericardial effusion is usually incidental, but cancer accounts for approximately one third of all cardiac tamponades. Drainage, which is mainly attained by pericardiocentesis, is needed when cancer or cancer treatment-related pericardial effusion leads to hemodynamic impairment. Placement of a pericardial catheter for 2-5 days is advised after pericardial fluid removal. In contrast, even a large pericardial effusion should be conservatively managed when the patient is stable, although the best frequency and timing of monitoring by echocardiography in this context are yet to be established. Pericardial effusion secondary to immune checkpoint inhibitors typically responds to corticosteroid therapy. Pericardiocentesis may also be considered to confirm the presence of neoplastic cells in the pericardial fluid, but the yield of cytological examination is low. In case of newly found pericardial effusion in individuals without active cancer and/or recent cancer treatment, a history of malignancy, unremitting or recurrent course, large effusion or presentation with cardiac tamponade, incomplete response to empirical therapy with nonsteroidal anti-inflammatory, and hemorrhagic fluid at pericardiocentesis suggest a neoplastic etiology.

Relationship between vitamin D status and left ventricular geometry in a healthy population: results from the Baltimore Longitudinal Study of Aging.

OBJECTIVES: The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular (LV) structure and function in community-dwelling subjects without heart disease. DESIGN: The relationship between concentrations of 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D reserve, and LV transthoracic echocardiography measures was analysed in 711 participants in the Baltimore Longitudinal Study of Aging who were without cardiac disease. RESULTS: Mean 25(OH)D in the study population was 32.3 ± 11.4 ng mL(-1) ; only 15.5% of subjects had moderate or severe vitamin D deficiency [25(OH)D < 20 ng mL(-1) ]. Adjusting for age, body mass index, cardiovascular disease risk factors, physical activity, calcium and parathyroid hormone, 25(OH)D was positively correlated with LV thickness (ß 0.095, SE 0.039, P < 0.05) and LV mass index (ß 7.5, SE 2.6, P < 0.01). A significant nonlinear relation between 25(OH)D and LV concentric remodelling was observed. LV remodelling was more likely in participants with 25(OH)D levels <30 ng mL(-1) [odds ratio (OR) 1.24; 95% confidence interval (CI) 0.83-1.85] or ≥38 ng mL(-1) (OR 1.73; 95% CI 1.13-2.65), compared with those with 30-37 ng mL(-1) 25(OH)D. Consistently, LV relative wall thickness was significantly lower (P for trend=0.05), and LV diastolic internal diameter index (P for trend<0.05) and end-diastolic volume index (P for trend<0.05) were significantly higher in subjects with 30-37 ng mL(-1) 25(OH)D compared to the rest of the study population. There was a significant interaction between 25(OH)D and hypertension on the risk of LV hypertrophy (P < 0.05). CONCLUSIONS: In a population-based sample of predominantly vitamin D-sufficient subjects without heart disease, LV geometry was most favourable at intermediate 25(OH)D concentrations.

Immunohistochemical localization and quantitative expression of somatostatin receptors in normal human spleen and thymus: Implications for the in vivo visualization during somatostatin receptor scintigraphy.

BACKGROUND: [111In-DTPA-D-Phe1]-octreotide scintigraphy allows the visualization of SRIF receptor (SSR)-expressing tumors, including thymic tumors, and normal tissues. While the spleen is clearly visualized, the thymus is not depicted, although both contain SSR. AIM: We evaluated whether the heterogeneity, the type, and the amount of SSR might explain this contrasting finding. MATERIALS, METHODS, AND RESULTS: By ligand-binding the number of [125I-Tyr11]-SRIF- 14 binding sites resulted comparable between the two tissues, whereas the number of [125I-Tyr3]-octreotide sites was significantly higher in the spleen (p<0.001). Quantitative RTPCR showed a significantly higher expression of sst2A mRNA in the spleen, whereas a significantly higher expression of SRIF and sst3 in the thymus. The highest density of sst2A in the spleen is in line with the in vivo uptake of [111In-DTPA-D-Phe1]- octreotide, which is considered a sst2-preferring ligand. The specificity is confirmed by the evidence that in vivo [111In-DTPA- D-Phe1]-octreotide uptake can be abolished during chronic administration of "cold" octreotide. Immunohistochemistry confirmed a preferential expression of sst2A on microenvironmental cells and of sst3 on lymphoid cells. CONCLUSIONS: The heterogeneity of SSR expression and the higher SRIF content explain the lack of thymus visualization during scintigraphy, whereas thymic tumors, which do not express SRIF, are visualized. Apart from the affinity of the radioligand, also the efficacy of the internalization is crucial for the in vivo uptake, and both heterogeneity and SRIF content affect this process. These observations might have an important impact when interpretating in vivo visualization of SSR-positive lesions, and when treatment with novel SRIF analogs is considered.

Onset of cutaneous vasculitis and exacerbation of IgA nephropathy after Bartonella henselae infection.

Bartonella henselae is the aetiological agent of cat-scratch disease. Recently, there have been reports of other conditions associated with this bacterium, including leucocytoclastic vasculitis, thrombocytopenic purpura, maculopapular and urticarial eruptions, granuloma annulare, erythema nodosum, erythema marginatum and erythema annulare. We report the first case, to our knowledge, of the simultaneous occurrence of cutaneous vasculitis and nephrotic syndrome in a 65-year-old woman with IgA nephropathy after a B. henselae infection transmitted by a cat scratch. The aetiopathogenetic role of B. henselae was hypothesized on the basis of the serological demonstration of acute B. henselae infection, the immunofluorescence findings, and the prompt resolution after azithromycin treatment. Patients reporting cat scratches or bites should undergo accurate clinical examination, routine laboratory examinations, urinalysis and clinical surveillance.

[Multimodal imaging in the differential diagnosis of soft tissue calcinosis]. / Imaging multimodale nella diagnosi differenziale della calcinosi dei tessuti molli.

Soft tissue calcinosis is a common radiographic finding, which may be related to different types of pathological processes. Multimodality imaging, combined with analysis of clinical and laboratory data, plays an important role for the differential diagnosis of these conditions. Conventional radiography is considered the first line approach to soft tissue calcinosis; CT and MRI may provide further information to better characterize calcified deposits. Imaging may help to distinguish metabolic calcification, such as primary tumoral calcinosis and the secondary one (associated with acquired disorders of calcium or phosphate regulation), from dystrophic calcification, which is associated to normal blood values of phosphate. The sedimentation sign typical of tumoral calcinosis has been demonstrated by plain film radiography, CT, MRI, and, more recently, by ultrasonography. Other types of soft tissue calcinosis may have a degenerative, metaplastic or neoplastic origin, and their characterization strongly relies on multimodality imaging.

High prevalence of vitamin D deficiency and its association with left ventricular dilation: an echocardiography study in elderly patients with chronic heart failure.

BACKGROUND AND AIMS: Vitamin D deficiency has been associated with chronic heart failure (CHF). We evaluated vitamin D levels in relationship with New York Heart Association (NYHA) classes, N-terminal pro-brain natriuretic peptide (NT-proBNP) values and left ventricular (LV) measures in ≥60 year old patients with stable CHF. Differently from previous investigations, LV function was assessed by transthoracic echocardiography, to provide easily reproducible results. METHODS AND RESULTS: The study was performed at geographic latitude 44° N, from March to May and from September to November 2008. Acute HF and diseases or drugs altering vitamin D status were exclusion criteria. NYHA scores and 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D and NT-proBNP concentrations were assessed in 90 (45 F, 45 M) Caucasian patients with CHF secondary to hypertension and/or coronary artery disease. Vitamin D levels were also measured in 31 subjects without heart disease (controls). LV echocardiography was performed in 52 (26 F, 26 M) representative patients. Vitamin D concentrations were significantly lower in CHF cases than in controls. Among subject with CHF, 97.8% presented vitamin D deficiency (25(OH)D<75 nmol/L), being severe (<25 nmol/L) in 66.7%. LV end-diastolic and end-systolic diameters were significantly longer, LV end-diastolic and end-systolic volumes bigger and fractional shortening lower in CHF patients with 25(OH)D<25 nmol/L than with 25(OH)D≥25 nmol/L (p<0.05). Log-values of 25(OH)D were negatively correlated with LV end-systolic diameter and volume (r=-0.28; p<0.05). On subgroup analysis, these results persisted only in male patients. CONCLUSIONS: In elderly CHF patients, vitamin D deficiency was highly prevalent and often severe. This first addressed echocardiography study showed a sex-specific association between vitamin D deficiency and LV dilation. Since further echocardiography data are easily obtainable, larger investigations are demanded.

Somatostatin receptor scintigraphy in thoracic diseases.

Somatostatin (SS) receptor scintigraphy is useful for the diagnosis of lesions with high density of SS receptors, and above all neuroendocrine tumors. For several years, only indium-labeled octreotide has been applied to visualise in vivo tissues with SS receptor overexpression. Radiolabeled octreotide became the gold standard for the detection of neuroendocrine tumors. More recently, however, several new SS analogues with varying affinity for SS receptor subtypes have been developed, and different radionuclides as radiolabels have been introduced. Moreover, significant improvements have been made by the introduction of hybrid machines, such as single photon emission computed tomography/ computed tomography (SPECT/CT) or positron emission tomography (PET)/CT that enable to perform whole-body imaging quickly and with high anatomical resolution in several body areas, including the chest. The development of more specific radiopharmaceuticals, together with the modern technique of imaging, may provide excellent quality images with high contrast, allowing to depict very small lesions and making them easy to interpret. Indeed, in the management of SS receptor-positive lesions, the contribution of nuclear medicine is essential in several clinical settings, such as initial diagnosis, disease staging, follow-up, treatment planning, and treatment monitoring. In addition, the tracer uptake might be used as a prognostic parameter and as a predictor of treatment response. In the chest, apart in (neuro)endocrine tumors, SS receptors have been demonstrated in granulomatous diseases, like sarcoidosis and other immune-mediated disorders, such as anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. In this paper we review and discuss the role of SS receptor scintigraphy in diagnosis, staging or follow- up of thoracic SS receptor-positive lesions.

Alterations in the autonomic control of heart rate variability in patients with anorexia or bulimia nervosa: correlations between sympathovagal activity, clinical features, and leptin levels.

Changes in body composition, hormone secretions, and heart function with increased risk of sudden death occur in eating disorders. In this observational clinical study, we evaluated sympathovagal modulation of heart rate variability (HRV) and cardiovascular changes in response to lying-to-standing in patients with anorexia (AN) or bulimia nervosa (BN) to analyze: a) differences in autonomic activity between AN, BN, and healthy subjects; b) relationships between autonomic and cardiovascular parameters, clinical data and leptin levels in patients with eating disorders. HRV, assessed by power spectral analysis of R-R intervals, blood pressure (BP) and heart rate (HR) were studied by tilt-table test in 34 patients with AN, 16 with BN and 30 healthy controls. Autonomic and cardiovascular findings were correlated with clinical data, and serum leptin levels. Leptin levels were lowered in AN vs BN and healthy subjects (p<0.0001), but both AN and BN patients showed unbalanced sympathovagal control of HRV due to relative sympathetic failure, prevalent vagal activity, impaired sympathetic activation after tilting, independently from their actual body weight and leptin levels. No significant correlations were obtained between HRV data vs clinical data, BP and HR findings, and leptin levels in eating disorders. Body mass indices (BMI) (p<0.02), and leptin levels (p<0.04) correlated directly with BP values. Our data showed alterations of sympathovagal control of HRV in eating disorders. These changes were unrelated to body weight and BMI, diagnosis of AN or BN, and leptin levels despite the reported effects of leptin on the sympathetic activity.

Myostatin mediates abdominal aortic atherosclerosis progression by inducing vascular smooth muscle cell dysfunction and monocyte recruitment.

Myostatin (Mstn) is a skeletal muscle growth inhibitor involved in metabolic disorders and heart fibrosis. In this study we sought to verify whether Mstn is also operative in atherosclerosis of abdominal aorta. In human specimens, Mstn expression was almost absent in normal vessels, became detectable in the media of non-progressive lesions and increased with the severity of the damage. In progressive atherosclerotic lesions, Mstn was present in the media, neointima, plaque shoulder and in infiltrating macrophages. Mstn co-localized with α-smooth muscle actin (α-SMA) staining and with some CD45+ cells, indicating Mstn expression in VSMCs and bloodstream-derived leukocytes. In vitro, Mstn was tested in VSMCs and monocytes. In A7r5 VSMCs, Mstn downregulated proliferation and Smoothelin mRNA, induced cytoskeletal rearrangement, increased migratory rate and MCP-1/CCR2 expression. In monocytes (THP-1 cells and human monocytes), Mstn acted as a chemoattractant and increased the MCP-1-dependent chemotaxis, F-actin, α-SMA, MCP-1 and CCR2 expression; in turn, MCP-1 increased Mstn mRNA. Mstn induced JNK phosphorylation both in VSMCs and monocytes. Our results indicate that Mstn is overexpressed in abdominal aortic wall deterioration, affects VSMCs and monocyte biology and sustains a chronic inflammatory milieu. These findings propose to consider Mstn as a new playmaker in atherosclerosis progression.

Characterization and sub-cellular localization of SS1R, SS2R, and SS5R in human late-stage prostate cancer cells: effect of mono- and bi-specific somatostatin analogs on cell growth.

Somatostatin (SST) and SST receptors (SS1R, SS2R, SS3R, SS4R and SS5R) appear to play a significant role in the progression of human prostate cancer (PCa), which is associated with heterogeneity of SSRs expression and specific cell localization as we already demonstrated in the LNCaP cell line, an in vitro model of human androgen-dependent PCa. In this study, PC-3 and DU-145 human castration-resistant PCa cells were found to express all SSRs, while LNCaP expressed all but SS4R. A 48-h treatment with BIM-23244 (SS2R/SS5R) or BIM-23926 (SS1R) SST analogs was more effective in inhibiting cell proliferation, compared to BIM-23120 (SS2R), BIM-23206 (SS5R) and BIM-23704 (SS1R/SS2R). BIM-23926 (SS1R) treatment increased the amount of p21 and decreased phosphorylated (p) ERK1/2. BIM-23244 (SS2R/SS5R) led to p21 increment only in PC-3 cells, and to pERK1/2 reduction in both cell lines. SS1R/SS2R and SS2R/SS5R receptor dimers were natively present on cell membrane and their amount was increased by BIM-23704 (SS1R/SS2R) or BIM-23244 (SS2R/SS5R) treatment, respectively. SS1R, SS2R and SS5R were differently distributed among nuclear, lysosomal and microsomal compartment, according to their different recycling dynamics. These results show that, in PC-3, DU-145 and LNCaP cells, activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effects.

Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines.

Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr1/sstr2, sstr2/sstr5, sstr5/dopamine (DA) type 2 receptor (D2R), and sstr2/D2R dimers. BIM-23704 (sstr1- and sstr2-preferential compound) increased the co-immunoprecipitation of sstr1/sstr2 and significantly inhibited proliferation (-30.98%). BIM-23244 (sstr2-sstr5 selective agonist) significantly increased the co-immunoprecipitation of sstr2/sstr5, and induced a -41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr2 and D2R and a moderate affinity for sstr5, significantly increased the sstr5/D2R and sstr2/D2R complexes and was the most powerful in inhibiting proliferation (-42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D2R/sstr5 and inhibiting cell proliferation (-30.54%). However, behind BIM-23A760, BIM-53097 (D2R-preferential compound) also significantly inhibited Calu-6 proliferation (-17.71%), suggesting a key role for D2R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.

Weight loss alters organ concentrations and contents of lead and some essential divalent metals in rats previously exposed to lead.

The loss of adipose tissue during energy restriction may be accompanied by a loss of lean body mass, including bone mass. Because most of the body lead burden is in the skeleton, we studied the effects of weight loss on the concentrations of lead in bone, blood and several organs in rats with prior but not current lead exposure. Concentrations of the essential divalent metals calcium, copper, iron, magnesium and zinc were also determined for comparison with lead. Lead-exposed rats (n = 25) were randomly assigned to one of three treatment groups: weight maintenance (WM), moderate weight loss (MWL) or substantial weight loss (SWL). For the two last-named groups, food intake was restricted for 4 wk to 70 and 40% of that of the WM group. Lead concentrations did not differ significantly (ANOVA, P > 0.05) among the three groups for blood, brain and bone. Significantly higher liver lead concentrations were observed in the SWL rats than in the WM and MWL groups. In general, organ concentrations of calcium, copper, magnesium and zinc were either lower or did not differ in the groups losing weight compared with the WM group. In contrast, organ Iron concentrations of the SWL group were higher than those of the other groups except in brain where there were no significant differences. The total liver content of lead was highest in the SWL group, but the lead content of other organs did not differ among the treatment groups. The contents of calcium, copper, magnesium and zinc generally were lower in the MWL and SWL groups than in the WM group in the liver and some of the other organs. The results demonstrate that weight loss can increase the quantity and concentration of lead in the liver, even in the absence of continued lead exposure. The data also demonstrate considerable differences among organ divalent metals in response to weight loss.