BACKGROUND: To assess the predictive role of lactate dehydrogenases (LDH) and fibrinogen (FBG) serum levels in metastatic colorectal cancer (mCRC) patients receiving a first-line bevacizumab-based therapy. OBJECTIVES: The aim of the present analysis was to retrospectively evaluate the role of basal and post-treatment LDH and FBG serum levels in predicting the clinical outcome of 139 mCRC patients receiving first-line chemotherapy in combination with bevacizumab. RESULTS: A statistically significant association between high pre-treatment LDH and FBG levels and progressive disease was observed with respect to low basal LDH and FBG patients. Furthermore, median progression-free survival was 7.3 versus 10.8 months and 7.3 versus 9.4 months for high and low LDH and FBG levels, respectively. Within the high LDH group, we observed a statistically significant reduction of LDH mean value compared with pre-treatment values in patients with objective response rate and stable disease. CONCLUSIONS: High LDH and FBG levels correlated with prognosis. A significant correlation between bevacizumab-based chemotherapy-induced reduction in LDH serum levels and response to treatment was observed within the high LDH group. These results, if confirmed in larger prospective studies, could be helpful for early identification of patients responsive to bevacizumab-based chemotherapy or candidate to more aggressive treatments

Bile acids (BAs) regulate the absorption of fat-soluble vitamins, cholesterol and lipids but have also a key role as singalling molecules and in the modulation of epithelial cell proliferation, gene expression and metabolism. These homeostatic pathways, when disrupted, are able to promote local inflammation, systemic metabolic disorders and, ultimately, cancer. The effect of hydrophobic BAs, in particular, can be linked with cancer in several digestive (mainly oesophagus, stomach, liver, pancreas, biliary tract, colon) and extra-digestive organs (i.e. prostate, breast) through a complex series of mechanisms including direct oxidative stress with DNA damage, apoptosis, epigenetic factors regulating gene expression, reduced/increased expression of nuclear receptors (mainly farnesoid X receptor, FXR) and altered composition of gut microbiota, also acting as a common interface between environmental factors (including diet, lifestyle, exposure to toxics) and the molecular events promoting cancerogenesis. Primary prevention strategies (i.e. changes in dietary habits and lifestyle, reduced exposure to environmental toxics) mainly able to modulate gut microbiota and the epigenome, and the therapeutic use of hydrophilic BAs to counterbalance the negative effects of the more hydrophobic BAs might be, in the near future, part of useful tools for cancer prevention and management.

PURPOSE: The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver exclude any role of contrast-enhanced ultrasound (CEUS) in the diagnosis of hepatocellular carcinoma (HCC) while the Italian Association for the Study of the Liver suggests its use for larger HCC. This study evaluated the accuracy of CEUS in comparison with computed tomography (CT) in the diagnosis of HCC and of residual of HCC after treatment. MATERIALS AND METHODS: We retrospectively evaluated 124 patients with 148 HCC nodules: 34 small (≤20 mm) and 114 large nodules (>20 mm). Ninety-three patients underwent treatment [one resection, 23 transcatheter arterial chemoembolisation (TACE), 37 radiofrequency ablation (RFA), 32 TACE/RFA combined with sorafenib]. The diagnosis of HCC on CEUS was confirmed by the typical pattern of arterial enhancement and portal and/or venous phase washout.RESULTS: We performed 90 CEUS for the initial diagnosis of HCC in 85 patients and 107 CEUS for the diagnosis of residual HCC after 1-month treatment in 92 patients. Sensitivity, specificity, positive predictive value, negative predictive value of CEUS and CT in the initial diagnosis of HCC were: 63 vs 92, 100 vs 100, 100 vs 100, 9 vs 25 for small HCC; 77 vs 92, 100 vs 100, 100 vs 100, 13 vs 22 for large HCC. In the diagnosis of residual of HCC, CEUS had a sensitivity of 70 % for small nodules and 76 % for large nodules, with an overall specificity of 100 %. CONCLUSION: CEUS is useful in the initial diagnosis and in the assessment of necrosis after RFA and TACE of HCC nodules

Introduction: Sorafenib is currently the only approved therapy in hepatocellular carcinoma (HCC). Alternative first- and second-line treatments are a significant unmet medical need, and several biologic agents have been tested in recent years, with poor results. Therefore, angiogenic pathways and the cytokine cascade remain possible targets in HCC. Recent studies suggest a role of epigenetic processes, associated with the initiation and development of HCC. In this field, DNA methylation, micro-RNAs (miRNAs) and tumor microenvironment cells became a possible new target for HCC treatment. Areas covered: This review explains the possible role of DNA methylation and histone deacetylase inhibitors as predictive biomarkers and target therapy, the extensive world of the promising miRNA blockade strategy, and the recent strong evidence of correlation between HCC tumors and peritumoral stroma cells. The literature and preclinic/clinic data were obtained through an electronic search. Expert opinion: Future research should aim to understand how best to identify patient groups that would benefit most from the prescribed therapy. To overcome the therapeutic stranding of HCC, a possible way out from the current therapeutic tunnel might be to evaluate the major epigenetic and genetic processes involved in HCC carcinogenesis, not underestimating the tumor microenvironment and its actors (angiogenesis, immune system, platelets). We are only at the start of a long journey towards the elucidation of HCC molecular pathways as therapeutic targets. Yet, currently this path appears to be the only one to cast some light at the end of the tunnel. © 2015 Taylor & Francis.

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patients.

BACKGROUND AND AIMS: Cholestasis is associated with systemic and hepatic oxidative and nitrosative stress; in this scenario, the conjugated hydrophilic bile salt ursodeoxycholate (UDCA) might play a protective role. METHODS: Circulating oxidative and nitrosative stress markers were assessed in patients with primary biliary cirrhosis (PBC) before and during UDCA (15-20mg/kg/day) therapy. RESULTS: In patients with stage I-II PBC, UDCA improved ALT and alkaline phosphatase levels and near normalized serum thioredoxin (1.97 ± 0.37 vs 2.41 ± 0.39 nmol/L), nitrotyrosine (15 ± 4 vs 22 ± 7 nmol/L), nitrosothiols (144 ± 28 vs 205 ± 84 nmol/L) and K-18 levels (162 ± 21 vs 228 ± 33 U/L). Conversely, less marked changes were noted in patients with stages III-IV who showed lower thioredoxin (1.01 ± 0.31 nmol/L), higher nitrosothiols (605 ± 64 nmol/L), nitrotyrosine (62 ± 13 nmol/L) and K-18 levels (521 ± 57 U/L). Overall, thioredoxin was inversely related with nitrotyrosine (r=-0.838, P<0.001) and K-18 (r=-0.838, P<0.001) levels. Nitrosothiols and K-18 were linearly and significantly related with nitrotyrosine (r=0.862, P<0.001; r=0.894, P<0.001, respectively). CONCLUSIONS: Oxidative and nitrosative changes in patients with PBC are effectively counteracted by UDCA. The protective effect of UDCA, however, are limited to early disease stages and progressively diminishes with ongoing cholestasis.

Objectives: The existence of specific features of Metabolic Syndrome (MetS) in psychiatric population in comparison to not psychiatric patients has not been systematically investigated. The purpose of this study is to evaluate the differences of MetS among a group of psychiatric patients and a group of internal medicine patients in terms of anthropometric measurements, biochemical variables, and cardiovascular risk. Methods: We enrolled 83 psychiatric inpatients under pharmacological treatment (schizophrenia n = 24, bipolar disorder n = 27, major depression n = 14, other n = 18) and 77 internal medicine patients visited for supposed MetS as affected by overweight or arterial hypertension. Results: Psychiatric patients differed from control subjects by age (yrs) (47 ± 9 vs. 52 ± 8.6, p = 0.001), waist circumference (cm) (111.9 ± 10.9 vs. 106 ± 12.6,p= 0.02), HDL cholesterol (mg/dl) (36.8 ± 7 vs. 48 ± 11.3, p = 0.001), serum insulin (μU/ml) (26 ± 12.5 vs. 16.4 ± 8.8, p = 0.001), triglyceride/HDL cholesterol ratio (4.8 ± 2.7 vs. 3.3 ± 2.2, p = 0.01). Female psychiatric patients had higher levels of triglycerides (mg) (178 + 86 vs. 115 + 53, p = 0.002) and of HOMA index (7.8 + 5 vs. 3.8 + 3.3, p = 0.005). Triglycerides and triglycerides/HDL ratio levels were higher in Unipolar Depression. A positive association was found between antidepressant drug treatment with triglycerides and triglycerides/HDL ratio levels, neuroleptic treatment with the HOMA index, and antipsychotics drugs with the Framingham index. Limitations: Psychiatric study population numerosity and duration of psychiatric illness and drug treatment. Conclusions: Specific features of MetS in psychiatric population are mainly represented by young age of onset, hyperinsulinemia, increased abdominal adiposity, and low HDL cholesterol whose common denominator may be insulin-resistance

In medicina umana è ben nota l’associazione tra obesità e alcune malattie croniche che definiscono la c.d. sindrome metabolica (SM). Il fattore riconosciuto come determinante nella SM è il grasso intra addominale ed è stata proposta l’ecografia per ottenere una misurazione pratica e diretta dello spessore del grasso regionale a questo livello. Sebbene studi recenti hanno dimostrato che l’obesità è associata con l’insulino-resistenza e la dislipidemia anche nel cane, in questa specie non è attualmente disponibile un metodo semplice e immediato per determinare la distribuzione regionale del grasso corporeo. Scopo del lavoro è di valutare la possibile applicazione dell’ecografia per quantificare il grasso addominale viscerale e per predire le alterazioni metaboliche nei cani obesi. In questo studio prospettico sono stati arruolati 54 cani di proprietà presentati per visita clinica di routine. Il metodo del body condition score (BCS) è stato utilizzato per definire i cani obesi, sovrappeso o normali. Differenti misure ecografiche del tessuto adiposo sono state effettuate; in particolare sono state proposte misure ecografiche dello stato di obesità basandosi su metodiche già accreditate in campo umano e confrontate con le misure ecografiche precedentemente proposte nel cane. Sono state dunque valutate l’adiposità addominale viscerale,, l’adiposità addominale sottocutanea e preperitoneale ed infine quella sottocutanea lombare. Le misure ecografiche così ottenute sono state comparate con i parametri morfometrici (BCS, circonferenza pelvica, % Body Fat) e metabolici (glucosio, colesterolo totale, HDL, LDL, trigliceridi, leptina e proteina C reattiva) di obesità. I dati sono stati analizzati statisticamente. L’analisi della correlazione tra le nuove misure ecografiche proposte e le misure cliniche del peso corporeo ha dimostrato una correlazione significativa sia del grasso viscerale che preperitoneale avevano con tutte le misure cliniche fatta eccezione per il peso. In particolare la misura ecografica del grasso viscerale era correlata positivamente n solo con il BCS e gli altri parametri morfometrici di obesità, ma anche con la concentrazione sierica del colesterolo totale, dell’HDL e della leptina. I risultati di questo studio suggeriscono che l’ecografia può essere un metodo utile pratico e non invasivo per quantificare i depositi di grasso regionale nei cani. In particolare la misura del grasso viscerale può essere utile nella diagnosi di obesità nella clinica pratica e può fornire utili informazioni sul rischio di disfunzione metabolica associata all’obesità nel cane (DMAO). Infatti fra le misure ecografiche testate in questo studio la misura del grasso viscerale sembra essere quella che meglio correla con i parametri metabolici come già dimostrato in campo umano suggerendo che questa misura ecografica potrebbe rappresentare un marker di rischio di DMAO.

Aims  The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, has been implicated in the pathogenesis of atherosclerosis. We therefore evaluated the genotyping of OLR1 gene in a sample of 55 patients with Metabolic Syndrome, a clinical condition characterized by a high cardiovascular risk. Methods and Patients  The genotyping of the LOX-1 was performed by polymerase chain reaction (PCR) analysis of the IVS4-14 A>G OLR1 polymorphism embedded within the OLR1 Linkage Disequilibrium block. Patients were assessed for routine serum parameters, microalbuminuria, insulin resistance (HOMA) and oxidative stress (thiobarbituric acid reactive substances, TBARs and thioredoxin). Results  The allele or genotype distribution of the OLR1 IVS4-14 A>G was not statistically different between MS and controls subjects. A positive association was found between IVS4-14 GG genotype, microalbuminuria and fasting glycaemia as well as a higher frequency of type 2 diabetes, elevated microalbuminuria, fasting serum glucose and HOMA index in the same subjects. Thioredoxin values were higher in patients with MS but did not differ in relation to OLR1 IVS4-14 A>G genotype. The TBARs/Cholesterol ratio was higher in MS both in IVS4-14 GG and in IVS4-14 AG. Conclusion  IVS4-14 GG genotype seems to be related to glucose metabolism disturbance, elevated insulin level and lipid peroxidation in patients with MS.

The aim of this prospective observational study was to investigate the variations of serum prolactin hormone (PRL) in a sample of 34 drug-naive patients (mean age 13 years) who started risperidone therapy assuming that several factors may favor the increase in serum PRL. Serum PRL and hyperprolactinemia clinical signs were examined at baseline (T0) and after almost 3 months of treatment (T1). We considered sex, pubertal status, risperidone dosage, psychiatric diagnosis, and any personal/family history of autoimmune diseases. The mean serum PRL value increased between T0 and T1 (P=0.004). The mean serum PRL was higher in females in the pubertal/postpubertal stage and for risperidone dosage up 1 mg/day. Hyperprolactinemia was found in 20% of patients at T0 and in 38% of patients at T1 (P=0.03). The mean serum PRL increase was greater in early-onset schizophrenia spectrum psychosis patients compared with no-early-onset schizophrenia spectrum psychosis patients (P=0.04). The increase in PRL was higher in patients with a personal and a family history of autoimmune diseases. This study suggests that the increase in serum PRL in patients treated with risperidone may be linked not only to the drug and its dosage but also to several risk factors such as sex, pubertal stage, psychiatric disease, and autoimmune disorders.

In some tumors, psychosocial interventions may enhance health-related quality of life (HRQOL) of patients. The effects of psychological variables on HRQOL in hepatocellular carcinoma (HCC) patients have been rarely assessed. The aim of this work is to evaluate the psychopathological profile of HCC and cirrhotic patients and its effect on HRQOL. Twenty-four HCC patients (median age 71, Child A 21, Child B 3), 22 cirrhotic patients (median age 68, Child A 20, Child B 2) and 20 control subjects were included in this study. Each subject completes four questionnaires: medical outcomes study short form-36 (SF-36, HRQOL evaluation); Hamilton-D (quantitative evaluation of depression; positive ≥8); symptom check list 90-revised (SCL 90-R, general psychopathological profile; nine domains, each positive >1); Toronto alexithymia scale (TAS 20) (positive ≥60). SCL 90-R: cirrhotic patients differ from HCC subjects for somatization (SOM) (M ± SD 1.09 ± 0.6 vs 0.65 ± 0.6; p = 0.01) and anxiety (M ± SD 0.85 ± 0.46 vs 0.58 ± 0.38; p = 0.01) items. TAS 20: positive in 50 % of HCC patients, in 54 % of cirrhotic patients (p = n.s.) and in none of controls. Hamilton-D: higher scores in cirrhotic patients than in the HCC group (86 vs 46 %; p = 0.005). SF-36: each item, except bodily pain, is lower in both group of patients in comparison with controls. Pearson correlation analysis shows negative correlations on HRQOL of depression, SOM and anxiety both in cirrhotic and HCC subjects, also of obsessive-compulsive and hostility items in HCC. This is the first report on the psychopathological profile of HCC patients: the results open questions on the role of psychological interventions that may improve HRQOL of patients before treatment and in the follow-up

OBJECTIVES: Different nuclear genes are thought to be involved in the regulation of the complex phenotype of metabolic syndrome (MS) and their number is increasing. A mutation in mitochondrial DNA (mtDNA), T4291C in transfer RNA isoleucine (tRNAile), has been associated with MS in a large American family. In addition, a mtDNA T16189C variant, already known to be associated with insulin resistance and type 2 diabetes mellitus in Caucasians, seems to underlie susceptibility to MS in the Chinese population. Our aim was to verify the T4291C and T16189C variants in subjects affected by different phenotypes of MS. METHODS: Seventy patients with MS and 35 healthy individuals were investigated for the presence of the mtDNA variants by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The T4291C variant was absent in patients and in controls. The T16189C variant was more frequent in patients with MS than in control subjects (21.4% versus 5.7%, P<0.04) and was associated with hypertension (P=0.01), waist circumference (P=0.02), body mass index (P=0.009), visceral fat thickness (P=0.04), homeostasis model assessment (P=0.03), and the number of MS diagnostic criteria (P=0.01). CONCLUSION: The mtDNA T16189C variant is associated with MS and its different clinical expressions. Prospective studies are warranted to establish the clinical relevance of this association. Copyright © 2011 Elsevier Inc. All rights reserved.

The p66(Shc) protein mediates oxidative stress-related injury in multiple tissues. Steatohepatitis is characterized by enhanced oxidative stress-mediated cell damage. The role of p66(Shc) in redox signaling was investigated in human liver cells and alcoholic steatohepatitis. HepG2 cells with overexpression of wild-type or mutant p66(Shc), with Ser(36) replacement by Ala, were obtained through infection with recombinant adenoviruses. Reactive oxygen species and oxidation-dependent DNA damage were assessed by measuring dihydroethidium oxidation and 8-hydroxy-2'-deoxyguanosine accumulation into DNA, respectively. mRNA and protein levels of signaling intermediates were evaluated in HepG2 cells and liver biopsies from control and alcoholic steatohepatitis subjects. Exposure to H2O2 increased reactive oxygen species and phosphorylation of p66(Shc) on Ser(36) in HepG2 cells. Overexpression of p66(Shc) promoted reactive oxygen species synthesis and oxidation-dependent DNA damage, which were further enhanced by H2O2. p66(Shc) activation also resulted in increased Erk-1/2, Akt and FoxO3a phosphorylation. Blocking of Erk-1/2 activation inhibited p66(Shc) phosphorylation on Ser(36). Increased p66Shc expression was associated with reduced mRNA levels of anti-oxidant molecules, such as NF-E2-related factor 2 and its target genes. In contrast, overexpression of the phosphorylation defective p66(Shc) Ala(36) mutant inhibited p66(Shc) signaling, enhanced anti-oxidant genes, and suppressed reactive oxygen species and oxidation-dependent DNA damage. Increased p66(Shc) protein levels and Akt phosphorylation were observed in liver biopsies from alcoholic steatohepatitis compared to control subjects.

The aim of this prospective observational study was to verify the tolerability and safety profile of risperidone in a sample of antipsychotic-naive children/adolescent patients having a different psychiatric diagnosis. Twenty-two (mean age of 12±3.2) antipsychotic-naive patients who started therapy with risperidone were recruited. The assessment involved anthropometric data (weight, height, BMI, BMI z-score and BMI percentile), cardiovascular parameters (blood pressure and QTc interval) and blood tests (levels of glucose, triglycerides, total cholesterol, glutamic oxaloacetic and pyruvic transaminases, γ-glutamyl transferase, prolactin, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, thyroglobulin, antithyroid peroxidase and antithyroglobulin). After an average follow-up of 6 months of risperidone therapy, a statistically significant increase in weight and body composition was observed. Furthermore, an increase in serum levels of prolactin was observed in 50% of patients. No other significant changes in metabolic and cardiovascular parameters were found. Although an increase in these parameters was detected, it remained in the normal range. This study suggests the use of specific protocols for monitoring children/adolescents treated with second-generation antipsychotics to manage the metabolic long-term complications and progression to more severe disease states

Sorafenib is recommended for the treatment of advanced-stage hepatocellular carcinoma (HCC). Nonetheless, it is expensive, effective in few patients, and may cause significant adverse effects. Therefore, accurate selection of patients is needed. In a previous study, we constructed a simple scoring system to predict patients' outcomes based on the occurrence of sorafenib adverse effects.

ABSTRACT: Aims The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, has been implicated in the pathogenesis of atherosclerosis. We therefore evaluated the genotyping of OLR1 gene in a sample of 55 patients with Metabolic Syndrome, a clinical condition characterized by a high cardiovascular risk. Methods and Patients The genotyping of the LOX-1 was performed by polymerase chain reaction (PCR) analysis of the IVS4-14 A>G OLR1 polymorphism embedded within the OLR1 Linkage Disequilibrium block. Patients were assessed for routine serum parameters, microalbuminuria, insulin resistance (HOMA) and oxidative stress (thiobarbituric acid reactive substances, TBARs and thioredoxin). Results The allele or genotype distribution of the OLR1 IVS4-14 A>G was not statistically different between MS and controls subjects. A positive association was found between IVS4-14 GG genotype, microalbuminuria and fasting glycaemia as well as a higher frequency of type 2 diabetes, elevated microalbuminuria, fasting serum glucose and HOMA index in the same subjects. Thioredoxin values were higher in patients with MS but did not differ in relation to OLR1 IVS4-14 A>G genotype. The TBARs/Cholesterol ratio was higher in MS both in IVS4-14 GG and in IVS4-14 AG. Conclusion IVS4-14 GG genotype seems to be related to glucose metabolism disturbance, elevated insulin level and lipid peroxidation in patients with MS.