Imaging of primary malignant tumors in non-cirrhotic liver.

Primary hepatic malignancies in non-cirrhotic liver include a wide spectrum of tumors, which are classified based on their cells of origin. Hepatocellular carcinoma is the most common primary malignant tumor, followed by intrahepatic cholangiocarcinoma. Beside these tumors, other primary malignancies in the non-cirrhotic liver are quite rare. Accurate diagnosis is often difficult with imaging alone and biopsy with further histopathological analysis is often necessary. However, many of these tumors exhibit suggestive or characteristic imaging features due to their different cellular components, allowing radiologists to suggest the correct diagnosis. Thus, the aim of this article is to provide an overview of imaging presentation of primary malignant liver tumors that develop in the non-cirrhotic liver, including potential differential diagnoses. Such knowledge is essential as it may contribute to accurate radiological diagnosis and improved patient outcome.

The Management of Geriatric and Frail HIV Patients. A 2017 Update from the Italian Guidelines for the Use of Antiretroviral Agents and the Diagnostic Clinical Management of HIV-1 Infected Persons.

OBJECTIVE: This article deals with the attempt to join HIV and geriatric care management in the 2017 edition of the Italian guidelines for the use of antiretrovirals and the diagnostic-clinical management of HIV-1 infected persons. METHODS: The outlined recommendations are based on evidence from randomized clinical trials and observational studies published in peer-reviewed journals and/or presented at international scientific conferences in recent years. The principles of starting antiretroviral therapy in elderly patients and the viro-immunological goals are the same as in the general HIV population. However, there are some specificities to consider, related to the host as well as the therapy itself. HIV care in elderly patients must shift from a combined AntiRetroviral Therapy specific approach to a more comprehensive management, and from a disease-based model (list of co-morbidities) to a multi-morbidity and frailty standpoint. The implementation of a geriatric approach, based on the Comprehensive Geriatric Assessment, is essential and consists of a broader evaluation of health status. This multidimensional and multidisciplinary evaluation is focused on the development of a tailored intervention plan. Polypharmacy is a frequent condition in the older population and an independent risk factor for negative health-related outcomes. This can be overcome with a multidisciplinary and cooperative approach involving HIV specialists, geriatricians and primary care physicians. CONCLUSION: The inclusion of geriatric care becomes necessary due to the novel needs of an evolving patient population. It is important to underline that the HIV specialist will continue to lead multidimensional interventions and optimize quality of care for HIV-positive people.

Distribution of IL28B Polymorphism in a Cohort of Italians and Immigrants with HCV Infection: Association with Viraemia, Stage of Fibrosis and Response to Treatment.

Aims of the study are to investigate, in a cohort of patients affected by HCV chronic hepatitis with genotypes 1 and 4, the prevalence of interleukin 28B (IL28B) genotypes, the possible association between IL28B polymorphism and severity of liver damage, the role of IL28B CC as a predictor of outcome. 365 patients with HCV infection were observed between 2013 and 2014. Demographic, virological, biochemical, and genetic characteristics of each patient were investigated. Liver fibrosis was assessed by transient elastometry. Mean age of the patients (72.9 % males, 27.1 % females) is 50 years. 91.5 % % of patients are Caucasian, 8.5 % African. In the patients with HCV1 and HCV4 a higher frequency of IL28B CT is observed with a prevalence of 52.1 and 61.8 % respectively. As regards ethnic group, African people have a prevalence of 35.5 % for CC, while Caucasians have a prevalence of 23.8 % for CC. In our cohort, IL28B polymorphism does not show significant differences among ethnic groups and in HCV1 and HCV4 genotypes. As described in literature, IL28B CC genotype is confirmed as predictor of sustained virological response in both Caucasians and Africans. A significant correlation between liver fibrosis and IL28B polymorphism emerges.

A cross-sectional analysis of daytime versus nocturnal polysomnographic respiratory parameters in cystic fibrosis during early adolescence.

BACKGROUND: In Cystic Fibrosis (CF), early detection and treatment of respiratory disease is considered the standard for respiratory care. Overnight polysomnography (PSG) may help identify respiratory deterioration in young patients with CF. METHODS: A prospective cohort study of 46 patients with CF, aged 8-12years, from a specialist clinic in a tertiary paediatric hospital. Daytime pulmonary function, shuttle test exercise testing and overnight PSG were studied. RESULTS: Of 81 children aged 8-12years, 46 (57%) agreed to participate. FEV1 (% predicted, mean 74.6%) was normal in 23 (50%), mildly abnormal in 12 (26.1%), moderately abnormal in 10 (21.7%) and severely abnormal in 1 (2.2%). Amongst sleep study parameters, FEV1 (% predicted) showed significant correlation with the respiratory rate (RR) in slow wave sleep (SWS), CO2 change in REM, baseline SaO2, and the arousal index (h-1). Backward, stepwise linear regression modelling for FEV1 (% predicted) included the entire group with a wide spectrum of clinical severity. From sleep, variables remaining in the multivariate model for FEV1 (F=16.81, p<0.001) were the RR in SWS (min-1) and the CO2 change in REM (p=0.003, and 0.014, respectively). When daytime tests were included, the variables remaining were RR in SWS and SD score for BMI (BMIsds) (F=18.70, p<0.001). CONCLUSIONS: Respiratory abnormalities on overnight sleep studies included elevated respiratory rates during SWS and mild CO2 retention in REM sleep, and these incorporated into a model correlating with FEV1 (% predicted). Thus, mild mechanical impairment of ventilation is evident on overnight sleep studies in children with cystic fibrosis although the significance of this finding will require further investigation.

Objectively measured sedentary behaviour and health and development in children and adolescents: systematic review and meta-analysis.

Sedentary behaviour has emerged as a unique determinant of health in adults. Studies in children and adolescents have been less consistent. We reviewed the evidence to determine if the total volume and patterns (i.e. breaks and bouts) of objectively measured sedentary behaviour were associated with adverse health outcomes in young people, independent of moderate-intensity to vigorous-intensity physical activity. Four electronic databases (EMBASE MEDLINE, Ovid EMBASE, PubMed and Scopus) were searched (up to 12 November 2015) to retrieve studies among 2- to 18-year-olds, which used cross-sectional, longitudinal or experimental designs, and examined associations with health outcomes (adiposity, cardio-metabolic, fitness, respiratory, bone/musculoskeletal, psychosocial, cognition/academic achievement, gross motor development and other outcomes). Based on 88 eligible observational studies, level of evidence grading and quantitative meta-analyses indicated that there is limited available evidence that the total volume or patterns of sedentary behaviour are associated with health in children and adolescents when accounting for moderate-intensity to vigorous-intensity physical activity or focusing on studies with low risk of bias. Quality evidence from studies with robust designs and methods, objective measures of sitting, examining associations for various health outcomes, is needed to better understand if the overall volume or patterns of sedentary behaviour are independent determinants of health in children and adolescents.

Hepatitis B virus mother-to-child transmission among HIV-infected women receiving lamivudine-containing antiretroviral regimens during pregnancy and breastfeeding.

The study included 309 HIV-infected pregnant women receiving a lamivudine-containing antiretroviral regimen from week 25 of gestational age until 6 months postpartum, during breastfeeding. Twenty-seven of them (8.7%) were hepatitis B virus surface antigen (HBsAg) positive; at baseline, hepatitis B virus (HBV) DNA levels >3 log(10) IU/mL (with a median level of 6.2 log(10) IU/mL) were found in 10 women, who at one, three and six months postpartum had median levels of 5.2 log(10) IU/mL, 4.5 log(10) IU/mL and 2.8 log(10) IU/mL, respectively. Twenty-four of the 30 breast milk samples evaluated had undetectable HBV DNA and the other six had values between 15 and 155 IU/mL. Median lamivudine concentrations were 1070 ng/mL in serum and 684 ng/mL in breast milk. Among the 24 HBV-exposed children with available samples, 16 always tested negative, four had a transient infection, one had an undetermined status and three (12.5%) first tested positive at Month 12 or Month 24. Among the children born to the HBV-uninfected mothers of the same cohort, the rate of HBsAg positivity at 12-24 months was 2% (4/196). Our finding of the absence of significative levels of HBV DNA in the breast milk of co-infected mothers supports the present recommendations for breastfeeding in HBV-infected women. Horizontal transmission can be hypothesized for the infections detected in children at 12-24 months. Children born to HBV-positive mothers remained at higher risk of postnatal HBV acquisition compared to those born to HBV-negative women.

A Simplified HAART Regimen with Raltegravir and Lamivudine, and Pharmacokinetic Interactions with a Combined Immunosuppressive Therapy with Tacrolimus and Everolimus in an HIV/HCV/HBV/HDV Patient after Liver Transplantation.

In this case report, we examine the impact of a simplified two-drug highly active antiretroviral therapy (HAART) regimen of raltegravir and lamivudine in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C, D and B viruses (HCV/HDV/HBV) under immunosuppressive therapy after liver transplantation. Pharmacokinetic interactions between integrase inhibitors and immunosuppressant drugs are described. Raltegravir, the first integrase inhibitor, associated with lamivudine, was introduced because its metabolism does not interfere with immunosuppressant therapy. During post-orthotopic liver transplantation follow-up, the patient's transaminases level increased and his antiretroviral therapy (HAART) of tenofovir/emtricitabine and fosamprenavir was changed, due to suspected drug toxicity. After seven months of follow-up, the patient showed good tolerance, good viro-immunological control with undetectable HIV viraemia and stable concentrations of immunosuppressive drugs. This case indicates that the combination of raltegravir and lamivudine is an optimal and effective strategy because it resulted in an important reduction of hepatic transaminases in a patient with very critical clinical conditions.

HIV-1 coreceptor switch during 2 years of structured treatment interruptions.

The purpose of this investigation was to determine the impact on human immunodeficiency virus (HIV) tropism of uncontrolled virus exposure during 2 years of intermittent highly active antiretroviral therapy (HAART). The Istituto Superiore di Sanità-Pulsed Antiretroviral Therapy (ISS-PART) randomized study compared the outcome of 2 years of structured treatment interruptions (STIs) versus standard continuous treatment in first-line HAART responder subjects. The STI schedule consisted of five STIs of 1, 1, 2, 2, and 3 months, respectively, separated by four periods of 3-month therapy. In the present study, coreceptor tropism was assessed in 12 patients of the STI arm at different time points over a period of 2 years. Tropism was determined on DNA and RNA by V3 loop region sequencing. The Geno2pheno algorithm (false-positive rate, FPR: 20%) was used for data interpretation. At baseline, 9/12 subjects (75.0%) had CCR5-tropic viruses in their HIV. Three had a CXCR4-tropic virus. Ten patients maintained the same coreceptor in DNA after 2 years, whereas in two patients, a shift occurred (one R5-X4, one X4-R5). In a patient with an R5 virus at baseline, a transient change to X4 tropism was seen in the rebounding virus during STI. Changes in tropism were not associated with the amplitude and duration of virus exposure during STIs, residual viremia at baseline, or the development of resistance mutations in the RT region. Our preliminary results suggest that viral replication, observed after short periods of treatment interruption, is not enough to drive the evolution of HIV tropism.

Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma.

BACKGROUND: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours. METHODS: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines. RESULTS: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments. CONCLUSION: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents.

Augmentation of clozapine with another pharmacological agent: treatment for refractory schizophrenia in the 'real world'.

OBJECTIVE: Refractory schizophrenia (SZ) affects approximately 30% of people with SZ. Clozapine (CLZ) is the gold standard treatment; however, there are still patients who are non-responsive or partially responsive to treatment. Although a lack of evidence exists in reality, these patients are treated with a combination of agents in addition to CLZ. Therefore, this article reviews the prevalence of the augmentation of CLZ with additional agents. METHOD: This study was cross-sectional; physicians in a region of Australia in May 2011 were contacted to provide details of their patients on CLZ and any additional agents. The data set consists of 84 patients. RESULTS: The majority of the patients 84.5% were taking at least one additional agent. Of those taking additional agents, they derived from the following classes' antipsychotics (72%), antidepressants (30%), mood stabilisers (17%), antimetabolic agents (13%), benzodiazepines (7%), anticholinergics (4%) and miscellaneous agents (12.5%). CONCLUSION: It is apparent that CLZ is routinely augmented with other agents despite the lack of an evidence base. However, concerning was the lack of augmentation with antimetabolic agents despite the paucity of literature reporting the detrimental impact of antipsychotic treatment upon patients metabolic indices. The findings are discussed in the context of the current recommendations and empirical literature.

Reason for clozapine cessation.

OBJECTIVE: Approximately 30% of individuals diagnosed with schizophrenia suffer from treatment-resistant or refractory schizophrenia. The gold standard for treatment of refractory schizophrenia is clozapine. However, a significant number of patients cease clozapine therapy; therefore this study explores patient's motives for cessation. METHOD: The motives for cessation and duration of clozapine treatment from a retrospective database of 151 patients with schizophrenia or schizo-affective disorder who had ceased clozapine once or more were reviewed, with the motives for cessation coded. The general motives for cessation were non-compliance, own decision, medical, poor response and other. In addition, the medical reasons for cessation were further codified: cardiac complications, neutropenia, fevers, other side effects and pregnancy. RESULTS: The majority of patients ceased clozapine owing to non-compliance with medical protocols or citing their own decision. Approximately half ceased after a period of 6 months or less. Seventeen per cent of patients ceased owing to medical reasons, with the largest proportions discontinuing treatment because of other side effects or neutropenia. CONCLUSION: Future research should seek to further investigate why patients decide to be non-compliant and formulate their own decision to cease treatment, as this will facilitate strategies to promote adherence amongst these two groups that are potentially the most amenable to change.

Human PrP90-231-induced cell death is associated with intracellular accumulation of insoluble and protease-resistant macroaggregates and lysosomal dysfunction.

To define the mechanisms by which hPrP90-231 induces cell death, we analyzed its interaction with living cells and monitored its intracellular fate. Treatment of SH-SY5Y cells with fluorescein-5-isothiocyanate (FITC)-conjugated hPrP90-231 caused the accumulation of cytosolic aggregates of the prion protein fragment that increased in number and size in a time-dependent manner. The formation of large intracellular hPrP90-231 aggregates correlated with the activation of apoptosis. hPrP90-231 aggregates occurred within lysotracker-positive vesicles and induced the formation of activated cathepsin D (CD), indicating that hPrP90-231 is partitioned into the endosomal-lysosomal system structures, activating the proteolytic machinery. Remarkably, the inhibition of CD activity significantly reduced hPrP-90-231-dependent apoptosis. Internalized hPrP90-231 forms detergent-insoluble and SDS-stable aggregates, displaying partial resistance to proteolysis. By confocal microscopy analysis of lucifer yellow (LY) intracellular partition, we show that hPrP90-231 accumulation induces lysosome destabilization and loss of lysosomal membrane impermeability. In fact, although control cells evidenced a vesicular pattern of LY fluorescence (index of healthy lysosomes), hPrP90-231-treated cells showed diffuse cytosolic fluorescence, indicating LY diffusion through damaged lysosomes. In conclusion, these data indicate that exogenously added hPrP90-231 forms intralysosomal deposits having features of insoluble, protease-resistant aggregates and could trigger a lysosome-mediated apoptosis by inducing lysosome membrane permeabilization, followed by the release of hydrolytic enzymes.

Adherence and genotypic drug resistance mutations in HIV-1-infected patients failing current antiretroviral therapy.

The aim of this study was to assess the correlation between the estimated adherence of HIV-1 infected patients with antiretroviral (ARV) therapy failure and drug-resistant mutations. We studied 40 patients with virological and immunological ARV-therapy failure. In order to assess the adherence of patients we used the SERAD questionnaire. Genomic sequencing of the HIV-1 pol gene was performed. 100% adherence was reported by 27 patients (67.5%) (adherent patients). Multivariate analysis showed that only baseline and nadir CD4+ counts maintained a significant correlation with the adherence. For PR and NNRTI mutations, we did not find any difference between the two groups of patients. Baseline NRTI mutations were higher in adherent patients than in non-adherent patients (p<0.05). No differences were found between plasma mutations and PBMC mutations. The authors conclude that genotypic resistance mutations were found in the majority of patients with ARV-therapy failure despite a good self-reported adherence to therapy. Adequate adherence to therapy is not the only key factor in viral suppression.

What to add in with metformin in type 2 diabetes?

This review considers the therapeutic choices currently faced by people with type 2 diabetes and those caring for them when glucose levels initially controlled with lifestyle management and metformin start to rise. While sulphonylureas are familiar agents and cheaper than other alternatives, they cause hypoglycaemia and modest weight gain, and robust outcome data are still lacking. Dipeptidyl peptidase 4 inhibitors ('gliptins') have an attractive pharmacological and adverse effect profile, but their effects on the cardiovascular system are also uncertain. Thiazolidinediones ('glitazones') are effective glucose-lowering agents, but cause weight gain and increase the risk of fracture, while the cardiovascular benefits hoped for in association with 'insulin-sensitization' have not been as expected. Glucagon-like peptide-1 agonists will not be acceptable as initial second-line agents for many people as they are injectable rather than oral. Well-powered 'head-to-head' clinical trials of adequate duration are therefore required to allow evidence-based decisions on second-line therapy.

The use of metformin in type 1 diabetes: a systematic review of efficacy.

AIMS/HYPOTHESIS: As adding metformin to insulin therapy has been advocated in type 1 diabetes, we conducted a systematic review of published clinical trials and clinical trial databases to assess the effects on HbA(1c), weight, insulin-dose requirement and adverse effects. METHODS: We constructed evidence tables and fitted a fixed-effects model (inverse variance method) in order to assess heterogeneity between studies and give a crude measure of each overall treatment effect. RESULTS: Of 197 studies identified, nine involved randomisation with informed consent of patients with type 1 diabetes to metformin (vs placebo or comparator) in either a parallel or crossover design for at least 1 week. We noted marked heterogeneity in study design, drug dose, age of participants and length of follow-up. Metformin was associated with reductions in: (1) insulin-dose requirement (5.7-10.1 U/day in six of seven studies); (2) HbA(1c) (0.6-0.9% in four of seven studies); (3) weight (1.7-6.0 kg in three of six studies); and (4) total cholesterol (0.3-0.41 mmol/l in three of seven studies). Metformin was well tolerated, albeit with a trend towards increased hypoglycaemia. Formal estimates of combined effects from the five trials which reported appropriate data indicated a significant reduction in insulin dose (6.6 U/day, p < 0.001) but no significant reduction in HbA(1c) (absolute reduction 0.11%, p = 0.42). No reported trials included cardiovascular outcomes. CONCLUSIONS/INTERPRETATION: Metformin reduces insulin-dose requirement in type 1 diabetes but it is unclear whether this is sustained beyond 1 year and whether there are benefits for cardiovascular and other key clinical outcomes.