Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study.

BACKGROUND: In monarchE, abemaciclib plus endocrine therapy (ET) as adjuvant treatment of hormone receptor-positive, human epidermal growth factor 2-negative, high-risk, early breast cancer (EBC) demonstrated a clinically meaningful improvement in invasive disease-free survival versus ET alone. Detailed safety analyses conducted at a median follow-up of 27 months and key patient-reported outcomes (PROs) are presented. PATIENTS AND METHODS: The safety population included all patients who received at least one dose of study treatment (n = 5591). Safety analyses included incidence, management, and outcomes of common and clinically relevant adverse events (AEs). Patient-reported health-related quality of life, ET symptoms, fatigue, and side-effect burden were assessed. RESULTS: The addition of abemaciclib to ET resulted in higher incidence of grade ≥3 AEs (49.7% versus 16.3% with ET alone), predominantly laboratory cytopenias [e.g. neutropenia (19.6%)] without clinical complications. Abemaciclib-treated patients experienced more serious AEs (15.2% versus 8.8%). Discontinuation of abemaciclib and/or ET due to AEs occurred in 18.5% of patients, mainly due to grade 1/2 AEs (66.8%). AEs were managed with comedications (e.g. antidiarrheals), abemaciclib dose holds (61.7%), and/or dose reductions (43.4%). Diarrhea was generally low grade (grade 1/2: 76%); grade 2/3 events were highest in the first month (20.5%), most were short-lived (≤7 days) and did not recur. Venous thromboembolic events (VTEs) were higher with abemaciclib + ET (2.5%) versus ET (0.6%); in the abemaciclib arm, increased VTE risk was observed with tamoxifen versus aromatase inhibitors (4.3% versus 1.8%). PROs were similar between arms, including being 'bothered by side-effects of treatment', except for diarrhea. At ≥3 months, most patients reporting diarrhea reported 'a little bit' or 'somewhat'. CONCLUSIONS: In patients with high-risk EBC, adjuvant abemaciclib + ET has an acceptable safety profile and tolerability is supported by PRO findings. Most AEs were reversible and manageable with comedications and/or dose modifications, consistent with the known abemaciclib toxicity profile.

RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in patients with untreated, EGFR-mutated, metastatic non-small cell lung cancer: Europe/United States subset analysis.

BACKGROUND: In EGFR mutation-positive NSCLC, dual EGFR/VEGFR inhibition compared to EGFR alone increases anti-tumor efficacy. The Phase III RELAY trial demonstrated superior PFS for ramucirumab plus erlotinib (RAM + ERL) over placebo plus erlotinib (PBO + ERL) (HR 0.591 [95% CI 0.461-0.760], p<0.0001). EGFR mutated NSCLC is less prevalent in Western versus Asian patients. This prespecified analysis evaluates efficacy and safety of RAM + ERL in EU and US patients enrolled in RELAY. PATIENTS AND METHODS: Patients were randomized 1:1 to ERL + RAM (10 mg/kg IV) or PBO Q2W. Treatment continued until unacceptable toxicity or progressive disease. Patients were stratified by geographic region (East Asia vs "other" [EU/US and Canada (EU/US)]). Objectives included PFS, ORR, DoR, OS, PFS2, safety and biomarker analysis. RESULTS: EU/US subset included 113/449 (25.9%) patients (58 RAM + ERL, 55 PBO + ERL). RAM + ERL improved PFS (20.6 vs 10.9 months, HR 0.605 [95% CI: 0.362-1.010]). ORR and DCR were similar, but median DoR was longer with RAM + ERL (18.0 vs 10.1 months, HR 0.527 [95% CI: 0.296-0.939]). OS and PFS2 were immature at data cut-off (censoring rates 81.0-81.8% and 67.3-79.3%, respectively). Most commonly reported Grade ≥3 TEAE for RAM + ERL was hypertension (17 [29.8%]) and for PBO + ERL, dermatitis acneiform (5 [9.1%]). CONCLUSION: EU/US subset analysis showed improved efficacy outcomes for RAM + ERL and a safety profile consistent with the overall population. Ramucirumab is a safe and effective addition to standard-of-care EGFR-TKI for EGFR mutation-positive metastatic NSCLC.

Hepatitis E Is a Rare Finding in Liver Transplant Patients With Chronic Elevated Liver Enzymes and Biopsy-Proven Acute Rejection.

BACKGROUND: In past decades, liver transplant (LT) patients were not routinely screened for hepatitis E virus (HEV) infection, and thus it might have been misdiagnosed as an acute rejection episode. Our aim was to analyze a real-world cohort of LT patients who presented with at least 1 episode of biopsy-proven acute rejection (BPAR) and suffered from persistent elevated transaminases, to evaluate the frequency of HEV infection misdiagnosed as a rejection episode. METHODS: Data from 306 patients transplanted between 1997 and 2017, including 565 liver biopsies, were analyzed. Biopsies from patients suffering from hepatitis C (n = 79; 25.8%) and from patients who presented with a Rejection Activity Index <5 (n = 134; 43.8%) were excluded. A subgroup of 74 patients (with 134 BPAR) with persistently elevated liver enzymes was chosen for further HEV testing. RESULTS: Positive HEV IgG was detectable in 18 of 73 patients (24.7%). Positive HEV RNA was diagnosed in 3 of 73 patients with BPAR (4.1%). Patients with HEV infection showed no difference in etiology of the liver disease, type of immunosuppression, or median Rejection Activity Index. CONCLUSION: Few HEV infections were misdiagnosed as acute rejection episodes in this real-world cohort. Thus, HEV infection is an infrequent diagnosis in cases with persistent elevated liver enzymes and BPAR after LT.

Regional frequency variation of revascularization procedures for carotid stenosis in Germany: Secondary data analysis of DRG data from 2012 to 2014.

BACKGROUND: For Germany, regional variation of procedure rates of carotid endarterectomy (CEA) and carotid artery stenting (CAS) performed for carotid stenosis have so far not been analyzed at a national level. The aim of this study was to assess small area estimates of procedure rates among German regions, and to identify regional characteristics, which are associated with the regional frequency of procedures. METHODS: German diagnosis-related groups (DRG) statistics (2012-2014) were analyzed. Inclusion and exclusion criteria for procedural codes were set according to German quality assurance measures in combination with the diagnosis of carotid stenosis (I65.2). Rates of CEA and CAS were indirectly standardized for sex and age. RESULTS: In total, 88,182 procedures were performed (73,042 CEA; 15,367 CAS). The overall procedure rate varied between 13.2 per 100,000 (Augsburg) and 89.2 per 100,000 (Wilhelmshaven). Spatial analysis revealed that regional distribution was significantly clustered. CONCLUSION: The rates of CEA, and especially of CAS showed high regional variation. The spatial distribution was significantly clustered. In addition to the regional prevalence of diabetes mellitus, smoking and obesity, socioeconomic factors, such as income and debts were correlated with the overall frequency of CEA and CAS. No significant association was found between indicators of health infrastructure (e. g. density of hospital beds, vascular surgeons and angiologists) and the overall procedure rate.

Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation.

BACKGROUND: Cardiovascular disease is a serious problem of liver transplant (LT) recipients because of increased cardiovascular risk due to immunosuppressive therapy, higher age, intraoperative risk and comorbidities (such as diabetes and nicotine abuse). Reported frequency of cardiovascular events after LT shows a high variability between different LT cohorts. Our aim was to analyze a cohort of LT recipients from a single center in Germany to evaluate frequency of the cardiovascular endpoints (CVE) myocardial infarction and/or cardiac death after LT and to investigate correlations of CVE post LT with pretransplant patient characteristics. PATIENTS: In total, data from 352 LT patients were analyzed. Patients were identified from an administrative transplant database, and all data were retrieved from patients' charts and reports. RESULTS: During the median follow-up of 4.0 (0-13) years, 10 cases of CVE were documented (six myocardial infarctions and four coronary deaths). The frequency of CVE did not differ according to classic cardiovascular risk factors such as body mass index (p=0.071), total cholesterol (p=0.533), hypertension (p=0.747), smoking (p=1.000) and pretransplant diabetes mellitus (p=0.146). In patients with pretransplant coronary heart disease (n=24; 6.8%) CVE were found more frequently (p=0.024). CONCLUSION: In summary, we found a rate of 2.8% CVE after LT in a German transplant cohort. Pretransplant CHD was the only risk factor for CVE, but showed no significant impact on overall survival.

Neutralization of mobile antiviral small RNA through peroxisomal import.

In animals, certain viral proteins are targeted to peroxisomes to dampen the antiviral immune response mediated by these organelles1-3. In plants, RNA interference (RNAi) mediated by small interfering (si)RNA is the main antiviral defence mechanism. To protect themselves against the cell- and non-cell autonomous effects of RNAi, viruses produce viral suppressors of RNA silencing (VSR)4, whose study is crucial to properly understand the biological cycle of plant viruses and potentially find new solutions to control these pathogens. By combining biochemical approaches, cell-specific inhibition of RNAi movement and peroxisome isolation, we show here that one such VSR, the peanut clump virus (PCV)-encoded P15, isolates siRNA from the symplasm by delivering them into the peroxisomal matrix. Infection with PCV lacking this ability reveals that piggybacking of these VSR-bound nucleic acids into peroxisomes potentiates viral systemic movement by preventing the spread of antiviral siRNA. Collectively, these results highlight organellar confinement of antiviral molecules as a novel pathogenic strategy that may have its direct counterpart in other plant and animal viruses.

[Locoregional solutions for groin defects : Coverage after vascular surgery]. / Lokoregionale Lösungen bei Leistendefekten : Deckung nach gefäßchirurgischen Eingriffen.

INTRODUCTION: Vascular surgery through a groin incision may be associated with severe wound healing disorders in this sensitive area. There are many options to reconstruct the defect surgically. The choice of surgical reconstruction depends mainly on the individual status of vasculature, which is most often compromised in these patients. There are random pattern flaps, as well as perforator, pedicled flaps or microvascular flaps to choose from. AIM: We give an overview of plastic surgical solutions for groin defects, with a special focus on complex wounds after vascular surgical complications. We discuss advantages and disadvantages of different flaps with two case reports and also show alternatives. PATIENTS AND METHODS: We demonstrate in two cases how the reconstruction of the groin defect was planned, taking into account the vascular status, and why we chose an innovative and seldom-used option in each case. RESULTS: The selected flaps, a pedicled fasciocutaneous ALT propeller flap and a perforator-based, pedicled abdominal advancement flap reconstructed the defects successfully. DISCUSSION: The surgical therapy for the reconstruction of groin defects should be chosen according to the individual vascular status to ensure safe and reliable blood supply. To guarantee the best possible reconstruction and avoid postoperative healing disorders and infections, less common flaps should also be considered.

Relationship between weight change and glycaemic control in patients with type 2 diabetes receiving once-weekly dulaglutide treatment.

AIM: To assess the relationship between weight change and glycated haemoglobin (HbA1c) change in dulaglutide-treated patients by analysing data from six head-to-head phase III AWARD clinical trials. METHODS: At 26 weeks, the relationship between weight and HbA1c was analysed in each trial rather than by pooling data because of differences in design and background therapy. The effect of baseline characteristics was also evaluated with regard to weight and HbA1c response. RESULTS: Across the studies, 87-97% and 83-95% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, had reductions in HbA1c levels, while 57-88% and 43-84% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, experienced weight loss. The majority (55-83%) of patients receiving dulaglutide 1.5 mg experienced weight loss and HbA1c reductions, while 41-79% of patients in the dulaglutide 0.75 mg arm lost weight and had reductions in HbA1c level. A weak and inconsistent correlation was observed between the changes in weight and HbA1c (range from -0.223 to 0.267) in patients treated with dulaglutide. The baseline characteristics of gender, age, duration of diabetes, HbA1c, body weight and BMI were not related to different combinations of weight and HbA1c responses. CONCLUSIONS: Dulaglutide is an effective treatment option across the type 2 diabetes treatment spectrum. Dulaglutide showed dose-dependent effects on both weight loss and HbA1c reduction. These effects had a weak correlation and appeared to be independent.

[Indications and results of endovascular therapy of critical limb ischemia]. / Indikationen und Ergebnisse der endovaskulären Therapie der kritischen Extremitätenischämie.

BACKGROUND: Critical limb ischemia (CLI) is the most severe form of peripheral artery occlusive disease and is characterized by high amputation, morbidity and mortality rates. Therefore, revascularization is the essential step in therapy for retention of the affected limb. OBJECTIVES: Although for a long time bypass surgery represented the gold standard in the treatment of CLI, in recent years there has been a disproportionate increase of endovascular treatment despite the lack of level-data. In this review the indications and results of endovascular therapy of CLI are presented on the basis of published data. METHODS: A literature search was carried out to identify publications that compared the results of endovascular and surgical therapy as well as observational studies about different endovascular techniques. RESULTS: The BASIL study provided the highest quality data comparing endovascular and surgical treatment of CLI. The long-term data of the BASIL trial showed that apart from patients with a suitable vein and a life expectancy of more than 2 years, first line endovascular therapy is equivalent to surgical treatment. The equivalence could also be demonstrated in a meta-analysis comparing operative and endovascular treatment of CLI. CONCLUSION: The CLI is a disease with high mortality and morbidity risks. Due to the comparable amputation-free survival times with lower complication rates in the published data, in most patients an endovascular first strategy in experienced centers can be justified.

Patient characteristics and outcomes of carotid endarterectomy and carotid artery stenting: analysis of the German mandatory national quality assurance registry - 2003 to 2014.

AIM: In Germany, every surgical or endovascular procedure on the extracranial carotid artery is documented in a mandatory quality assurance registry. The purpose of this study is to describe the patient characteristics, the indications for treatment, and the short-term outcomes as well as to analyse the corresponding trends from 2003 to 2014. METHODS: Data on demographics, peri-procedural measures, and outcomes were extracted from the annual quality reports published by the Federal Agency for Quality Assurance and the Institute for Applied Quality Improvement and Research in Health Care. Data were available from 2003 to 2014 for carotid endarterectomy (CEA) and from 2012 to 2014 for carotid artery stenting (CAS). The primary outcome event of this study is any stroke or death until discharge from hospital. Temporal trends of categorical variables were statistically analysed using the Cochran-Armitage test for trend. RESULTS: Between 2003 and 2014, 309,405 CEAs and 18,047 CAS procedures were documented in the database; 68.1% of all patients were male. The mean age of patients treated with CEA increased from 68.9 years in 2003 to 70.9 years in 2014. The proportion of patients with ASA stages III to V increased from 65% to 71% in CEA, whereas it decreased from 44% to 41% in CAS patients. 53.1% of all CEAs were performed for asymptomatic patients (group A), 34.4% for symptomatic patients treated electively (group B), and 11.2% a in a collective group including other indications for CEA or CAS (such as recurrent stenosis, carotid aneurysms, emergency treatment due to stroke-in-evolution). The corresponding data for CAS are 49.3%, 26.1% and 26.3% respectively. In group B, the interval between the neurological index event and CEA decreased from 28 to 8 days (P<0.001). In patients treated with CAS, this interval was 9 days in 2012 (no further data available). On average, 67.1% and 48.2% of surgically treated patients as well as 77.8% and 69.8% of CAS patients were neurologically assessed before and after the procedure, respectively. From 2003 to 2014, CEA procedures were performed more frequently in locoregional anesthesia (10.1% to 29.1%, P<0.001). The same trend was observed for the application of the eversion technique (37.0% to 41.6%, P<0.001), the neurophysiological monitoring (49.8% to 61.8%, P<0.001), and the intra-procedural assessment of the treated artery (44.5% to 69.7%, P<0.001). In contrast, shunting was used less frequently (48.1% to 43.0%, P<0.001). Averagely 95.7% of all endovascular procedures were performed using stent-angioplasty. In 54.2% a protection device was used. Nitinol and bare metal stents were used in 74.1% and 21.4% of cases, respectively. The in-hospital rate of any stroke or death decreased from 2.0% to 1.1% in asymptomatic patients treated with CEA without a contralateral stenosis ≥75% or occlusion, P<0.001). In patients treated with CAS this rate did not increase (1.7% to 1.8%, p=0.909). The corresponding rates in CEA and CAS patients with severe contralateral stenosis or occlusion varied between 1.9%-3.1% and 2.2%-2.6%, respectively. In symptomatic patients (group B) with a stenosis of 50 percent or more, the rate of any stroke or death decreased significantly after CEA from 4.2% to 2.4% (P<0.001) and remained stable after CAS (3.9% to 3.5%, P=0.577). CONCLUSION: This report on 327,452 carotid procedures analysed one of the largest quality registries on CEA and CAS worldwide. Data indicate that treated patients became older and sicker, whereas in contrast, the in-hospital rates of stroke or death are decreasing over time.

Stroke risk in the early period after carotid related symptoms: a systematic review.

Current guidelines recommend performing carotid endarterectomy in patients with symptomatic carotid disease as soon as possible after the neurological index event. However, early stroke risk has not been well documented for this patient group. We therefore conducted a systematic analysis of the current literature on the recurrent risk of ischemic events in patients with symptomatic carotid stenosis. Systematic review was performed by searching the MEDLINE® database from 1950 until June 8, 2015 (key words: cerebral ischemia, transient ischemic attack, amaurosis fugax, stroke, symptomatic carotid stenosis, recurrent risk, outcome, prognosis, follow-up, cohort and natural history). All studies reporting stroke risks in patients with symptomatic carotid stenosis after neurologic index events within a period of 7 days were included. Cumulative stroke risks with 95% confidence intervals after a neurologic index event were recalculated at 2-3, 7, 14 and 30 days and a meta-analysis including an analysis of heterogeneity were performed using the statistical package R and Excel for Mac 2003. Ten studies with a total number of 2634 patients were included. Results of an overall stroke risk were as follows: 2.0-17.2% at 2-3 days, 0-22.1% at 7 days, 0-29.6% at 14 days and 0-11.1% at 30 days in patients with a symptomatic extracranial carotid stenosis. The pooled stroke risk in the six studies with active follow-up was 6.0% (95% CI 2.4-14.4) at 2-3 days, 10.9% (6.1-18.7) at 7 days and 17.6% (9.7-29.9) at 14 days. Pooled stroke risk in the three studies with uncensored populations was even higher with 6.4% (1.5-23.8%) at 2-3 days, 19.5% (12.7-28.7) at 7 days and 26.1% (20.6-32.5%) at 14 days. Significant heterogeneity (P<0.001) could be explained by the different inclusion criteria and the study's design. Retrospective studies with passive follow-up had the lowest stroke risk whereas prospective studies with active follow-up and without bias through early intervention by carotid endarterectomy or carotid stenting had the highest stroke risk. The risk of recurrence of cerebrovascular events in patients with symptomatic carotid stenosis within the first days after a neurologic index event is as high as 6.4% (1.5-23.8), 19.5% (12.7-28.7) and 26.1% (20.6-32.5) after 2-3, 7 and 14 days respectively. Patients with a symptomatic carotid stenosis are therefore at a very high risk of a definitive stroke. Recommendations by current guidelines to perform carotid endarterectomy as soon as possible after the neurologic index event are therefore justified.

Análise produtiva e econômica de suínos criados nos sistemas wean-to-finish e convencional de produção / Productive and economic analysis of pigs raised in wean-to-finish and conventional production systems

O modelo de produção de suínos denominado Wean-to-Finish (WF) é considerado uma alternativa que busca alcançar melhor desempenho produtivo, redução de estresse aos animais e melhorias na logística. Nesse sistema, os leitões são desmamados e transferidos diretamente a um galpão WF (creche-crescimento-terminação), onde permanecem até o abate. Com o objetivo de avaliar os comportamentos produtivo e econômico de suínos alojados no sistema WF em comparação ao sistema convencional de produção (CC), foram avaliados dois grupos de suínos provenientes das mesmas unidades produtoras de leitões, nascidos e desmamados na mesma semana. Um grupo foi alojado em uma creche do sistema convencional de produção (grupo CC), e o outro em um galpão WF adaptado (grupo WF), ambos em baias coletivas. Para análise de produção, foram calculados o consumo médio diário de ração (CMDR), o ganho de peso médio diário (GPMD) e a conversão alimentar (CA). Para análise econômica, foi determinado o custo por quilograma de ganho de peso vivo. Os dados foram submetidos à análise de variância utilizando-se o pacote estatístico SAS, previamente testados para normalidade dos resíduos pelo teste de Shapiro-Wilk, e as médias dos grupos comparadas pelo teste de Tukey (5%). Na fase de creche, o GPMD foi de 0,468 e 0,449, e a CA de 1,48 e 1,42 para os Grupos WF e CC, respectivamente. Nas fases de crescimento e terminação, o GPMD foi de 0,924kg no grupo WF e de 0,909kg no grupo CC. A conversão alimentar foi de 2,41 para ambos os grupos, não sendo diferentes estatisticamente entre si (P>0,05) nas diferentes fases de produção nos parâmetros analisados. No aspecto econômico, o grupo WF apresentou os menores custos, com diferença de R$ 0,08 por quilograma de ganho de peso vivo em comparação ao grupo CC. Os resultados do desempenho produtivo associado ao aspecto econômico indicam que o sistema WF pode ser uma alternativa viável dentro da cadeia produtiva de suínos.

The pig production model called "Wean-to-Finish" (WF) is considered an alternative to better productive performance, reducing stress to the animals and improvements in logistics. In this system, the piglets are weaned and transferred directly to a WF shed (nursery-grower-finisher), where they remain until slaughter. Aiming to evaluate the productive and economic behavior of pigs housed in the WF system compared to conventional production system (CC), two groups of pigs from the same sow farm, born and weaned in the same week were evaluated. One group was housed in a conventional nursery production system (CC group) and the other in a WF shed adapted (WF group), both in collective pens. For analysis of the average production, average daily feed intake (ADFI), average daily weight gain (ADWG) and feed conversion ratio (FCR) were calculated. For economic analysis the cost per kilogram of live weight gain was determined. Data were subjected to analysis of variance using the SAS statistical package, previously tested for normality of the residuals using the Shapiro-Wilk test, and the means of groups were compared by the Tukey test (5 %). In the nursery phase ADWG was 0.468 and 0.449, and the FCR was 1.48 and 1.42 for the WF and CC groups respectively. During the growing and finishing ADWG was 0.924kg in the WF group and 0.909 in the CC group. The FCR was 2.41 for both groups, not being statistically different from each other (P>0.05) at different stages of production in the analyzed parameters. In the economic aspect, the WF group had the lowest costs, with a difference of R$ 0.08 per kilogram of live weight gain compared to the CC group. The results of productive performance associated with the economic aspect indicate that the WF system can be a viable alternative in the pig production chain.

New onset of diabetes after transplantation is associated with improved patient survival after liver transplantation due to confounding factor.

BACKGROUND: The influence of NODAT on survival of liver transplant recipients has not been clarified. Therefore, we evaluated the effect of NODAT on survival in LT recipients. METHODS: Data from 352 LT patients were totally analyzed. 97 patients with pretransplant diabetes mellitus were excluded, and 255 patients without diabetes mellitus at time of transplantation were included. RESULTS: NODAT was diagnosed in 41 patients (16.1%). There was no difference in frequency of NODAT according to the etiology of liver cirrhosis. NODAT was associated with a higher body weight (p=0.004) and BMI (p=0.002) 5years after LT, but not with weight gain (p=0.201) or increase in BMI (p=0.335) 5years after LT. HbA1c 5years after LT was significantly higher in patients with NODAT (p=0.001), but mean HbA1c still remained lower than 6.5% (6.4(±1.2) %). Patients with NODAT showed better survival rates (log rank: p=0.002) compared to LT recipients without diabetes. According to all existing knowledge of diabetes mellitus (DM) better survival cannot be a direct effect of this disease. Our results are rather influenced by an not known confounding factor (possibly recovery from cachexia) associated with better survival and NODAT, while complications of NODAT will not appear during the relatively short postoperative time and observation period (mean follow up 6.08 (±2.67) years). CONCLUSION: NODAT is frequently diagnosed in LT recipients and is associated with an improved 5year survival after LT due to a not exactly known confounding factor.

Alternation of histone and DNA methylation in human atherosclerotic carotid plaques.

Little is known about epigenetics and its possible role in atherosclerosis. We here analysed histone and DNA methylation and the expression of corresponding methyltransferases in early and advanced human atherosclerotic carotid lesions in comparison to healthy carotid arteries. Western Blotting was performed on carotid plaques from our biobank with early (n=60) or advanced (n=60) stages of atherosclerosis and healthy carotid arteries (n=12) to analyse di-methylation patterns of histone H3 at positions K4, K9 and K27. In atherosclerotic lesions, di-methylation of H3K4 was unaltered and that of H3K9 and H3K27 significantly decreased compared to control arteries. Immunohistochemistry revealed an increased appearance of di-methylated H3K4 in smooth muscle cells (SMCs), a decreased expression of di-methylated H3K9 in SMCs and inflammatory cells, and reduced di-methylated H3K27 in inflammatory cells in advanced versus early atherosclerosis. Expression of corresponding histone methyltransferases MLL2 and G9a was increased in advanced versus early atherosclerosis. Genomic DNA hypomethylation, as determined by PCR for methylated LINE1 and SAT-alpha, was observed in early and advanced plaques compared to control arteries and in cell-free serum of patients with high-grade carotid stenosis compared to healthy volunteers. In contrast, no differences in DNA methylation were observed in blood cells. Expression of DNA-methyltransferase DNMT1 was reduced in atherosclerotic plaques versus controls, DNMT3A was undetectable, and DNMT3B not altered. DNA-demethylase TET1 was increased in atherosclerosisc plaques. The extent of histone and DNA methylation and expression of some corresponding methyltransferases are significantly altered in atherosclerosis, suggesting a possible contribution of epigenetics in disease development.

Ultrasound surveillance after CAS and CEA: what's the evidence?

AIM: The rationale of clinical and Duplex ultrasound (DUS) surveillance after carotid endarterectomy (CEA) and carotid artery stenting (CAS) is the detection of recurrent stenoses and the prevention of future carotid-related cerebral ischemic events. This paper addresses the evidence for this approach. METHODS: The multicenter randomized controlled trials (RCTs) published between 1990 and 2013 were reviewed with respect to DUS surveillance intervals, recurrent stenoses rates and recurrent ipsilateral stroke rates. In addition a Medline literature search from January 1990 until February 2014 was performed by use of the following keywords: "surveillance"; "carotid endarterectomy"; "carotid stenting"; "carotid artery surveillance"; "carotid artery stenosis". Finally we analyzed all carotid-related guidelines published between 2006 and 2013 for recommendations on DUS surveillance after CEA or CAS. RESULTS: Nine RCT protocols (NASCET, ECST, ACST, ACAS, CAVATAS, SAPPHIRE, EVA-3S, CREST, and SPACE) showed similar follow-up intervals (at 1 month, 3 or 4 and at 6, and 12 months after CAS and CEA, then at least once a year). The incidence of a recurrent carotid stenosis (≥50%) or occlusion ranged around 6% four years after CEA or CAS. The annual incidence of any ipsilateral cerebral ischemic event was about 1% and 0.5% after CEA for a symptomatic or an asymptomatic stenosis respectively. Since the overall incidence of carotid recurrent stenosis and postprocedural strokes is low, DUS is questioned as necessary for all patients after CEA and CAS in prospective single center series. However, certain subgroups of patients (women, diabetics, patients with dyslipidemia, smokers) might have increased rates of restenosis after CEA or CAS. Data on DUS surveillance intervals following CAS is rare. Three out of 21 identified guidelines recommend long-term DUS surveillance, as the benefits are considered to exceed the risks. However, the level of evidence for any recommendation on DUS surveillance is consistently low. CONCLUSION: Our literature review reveals only little evidence to support routine DUS after CEA within short intervals. Currently a practice with one periprocedural DUS and one DUS after 12 months after CEA seems to be reasonable. In patients with an ipsilateral restenosis≥50%, contralateral disease progression≥50% and in patients who are considered to be at higher risk of restenosis further DUS surveillance seems appropriate. Due to inconsistent long-term data on surveillance after CAS imaging at 6 months and then annually seems reasonable. Further studies on DUS surveillance are necessary.

[The transition of palliative care from the hospital to the ambulatory care of the general practitioner: the experience in the canton of Fribourg]. / Soins palliatifs: de l'hôpital de soins aigus au cabinet du praticien. L'expérience fribourgeoise.

Thanks to medical progress, the life expectancy of a majority of severely ill patients has greatly improved. The fact that these patients will live longer with their disease encourages new solutions to respond to the challenges of care continuity, coordination, interprofessional and interinstitutional collaboration. Palliative care represents a chain management based on the involvement of every professional in acute care hospitals, palliative care units, nursing homes and private homes. The collaboration among the different players as well as their education are essential elements linked to the quality of care, to the quality of life for both patients and their relatives.

Constitutive and inducible co-expression systems for non-viral osteoinductive gene therapy.

Tissue regenerative gene therapy requires expression strategies that deliver therapeutic effective amounts of transgenes. As physiological expression patterns are more complex than high-level expression of a singular therapeutic gene, we aimed at constitutive or inducible co-expression of 2 transgenes simultaneously. Co-expression of human bone morphogenetic protein 2 and 7 (BMP2/7) from constitutively expressing and doxycycline inducible plasmids was evaluated in vitro in C2C12 cells with osteocalcin reporter gene assays and standard assays for osteogenic differentiation. The constitutive systems were additionally tested in an in vivo pilot for ectopic bone formation after repeated naked DNA injection to murine muscle tissue. Inductor controlled differentiation was demonstrated in vitro for inducible co-expression. Both co-expression systems, inducible and constitutive, achieved significantly better osteogenic differentiation than single factor expression. The potency of the constitutive co-expression systems was dependent on relative expression cassette topology. In vivo, ectopic bone formation was demonstrated in 6/13 animals (46% bone formation efficacy) at days 14 and 28 in hind limb muscles as proven by in vivo µCT and histological evaluation. In vitro findings demonstrated that the devised single vector BMP2/7 co-expression strategy mediates superior osteoinduction, can be applied in an inductor controlled fashion and that its efficiency is dependent on expression cassette topology. In vivo results indicatethatco-expression of BMP2/7 applied by non-viral naked DNA gene transfer effectively mediates bone formation without the application of biomaterials, cells or recombinant growth factors, offering a promising alternative to current treatment strategies with potential for clinical translation in the future.

Preoperative left ventricular hypertrophy is associated with reduced patient survival after liver transplantation.

UNLABELLED: Left ventricular hypertrophy (LVH) has been described in the context of cirrhotic cardiomyopathy. The influence of LVH on survival of liver transplant (LT) recipients has not been clarified. Therefore, we evaluated the effect of LVH on survival in LT recipients. In total, data from 352 LT patients were analyzed. LVH was diagnosed by echocardiographic measurement of left ventricular wall thickness before LT. Patients were followed up for a mean of 4.2 yr. LVH was diagnosed in 135 (38.4%) patients. Patients with LVH had significantly more frequently male gender (p = 0.046), diastolic dysfunction (p < 0.001), and hepatocellular carcinoma (HCC; p = 0.004). Furthermore, LVH patients were older (p < 0.001) and had a higher body mass index (BMI; p = 0.001). There was no difference in frequency of arterial hypertension, pre-transplant diabetes mellitus, or etiology of liver cirrhosis. Patients without LVH had a better survival (log rank: p = 0.05) compared with LVH patients. In a multivariate Cox regression LVH (p = 0.031), end-stage renal disease (ESRD; p = 0.003) and lack of arterial hypertension (p = 0.004) but not MELD score (p = 0.885) were associated with poorer survival. CONCLUSION: LVH is frequently diagnosed in patients on the waiting list and influences survival after LT.

Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value.

BACKGROUND: The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown. METHODS: DNA-dependent protein kinase catalytic subunit, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT-PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan-Meier curves and multivariate Cox model were used to study the impact on clinical outcome. RESULTS: Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC proliferation, genomic instability and microvessel density, and negatively with apoptosis and patient's survival. Proliferation decline and massive apoptosis followed DNA-PKcs silencing in HCC cell lines. Total and phosphorylated HSF1 protein, mRNA and activity were upregulated in HCC. Mechanistically, we demonstrated that HSF1 induces DNA-PKcs upregulation through the activation of the MAPK/JNK/AP-1 axis. CONCLUSION: DNA-dependent protein kinase catalytic subunit transduces HSF1 effects in HCC cells, and might represent a novel target and prognostic factor in human HCC.

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.