Clinical outcomes for sirolimus-eluting stent implantation and vascular brachytherapy for the treatment of in-stent restenosis.

The purpose of this study was to compare the mid-term clinical outcome of sirolimus-eluting stent (SES) implantation and vascular brachytherapy (VBT) for in-stent restenosis (ISR). We assessed the 9-month occurrence of major adverse cardiac events (MACE) in 44 consecutive patients with ISR treated with SES implantation and 43 consecutive patients treated with VBT in the period immediately prior. Baseline clinical and angiographic characteristics of the two groups were similar. During follow-up, three patients (7%) died in the VBT group and none in the SES group. The incidence of myocardial infarction was 2.3% in both groups. Target lesion revascularization was performed in 11.6% of the VBT patients and 16.3% of the SES patients (P = NS). The 9-month MACE-free survival was similar in both groups (79.1% VBT vs. 81.5% SES; P = 0.8 by log rank). The result of this nonrandomized study suggests that sirolimus-eluting stent implantation is at least as effective as vascular brachytherapy in the treatment of in-stent restenosis.     

Strategies for improving the outcomes of small-for-size grafts in adult-to-adult living-donor liver transplantation

Living-donor liver transplantation (LDLT) has been refined and accepted as a valuable treatment for patients with end-stage liver disease in order to overcome the shortage of organs and mortality on the waiting list. However, graft size problems, especially small-for-size (SFS) grafts, remain the greatest limiting factor for the expansion of LDLT, especially in adult-to-adult transplantation. Various attempts have been made to overcome the problems regarding SFS grafts, such as increasing the graft liver volume and/or controlling excessive portal inflow to a small graft, with considerable positive outcomes. Recent innovations in basic studies have also contributed to the treatment of SFS syndrome. Herein, we review the literature and assess our current knowledge of the pathogenesis and treatment strategies for the use of SFS grafts in adult-to-adult LDLT.     

Usefulness of Technetium-99 m-2-methoxy-isobutyl-isonitrile liver scintigraphy for evaluating disease activity of non-alcoholic fatty liver disease

Aim: Non‐alcoholic steatohepatitis (NASH) is a progressive form of non‐alcoholic fatty liver disease (NAFLD). Therefore, it is important to evaluate disease activity and distinguish NASH from simple steatosis in NAFLD. Technetium‐99 m‐2‐methoxy‐isobutyl‐isonitrile (^99mTc‐MIBI) is a lipophilic cation designed for myocardial perfusion scintigraphy in the diagnosis of ischemic heart diseases, and its retention reflects mitochondrial function. It was reported that hepatic mitochondrial abnormalities would be an important predictive factor for NASH disease progression. The aim of this study was to examine the clinical usefulness of ^99mTc‐MIBI liver scintigraphy for evaluating disease activity of NAFLD and distinguishing NASH from simple steatosis in patients with NAFLD. Methods: Twenty‐six patients with biopsy‐proven NAFLD were enrolled. Clinicolaboratory tests and ^99mTc‐MIBI liver scintigraphy were performed. To evaluate hepatic uptake, regions of interest were set at the liver and heart, and the uptake ratio of the liver to heart (liver/heart ratio) was calculated. Results: All patients with NAFLD were classified into three groups according to the NAFLD activity score: non‐NASH (simple steatosis) (n = 4), borderline NASH (n = 11), and NASH (n = 11). Liver/heart ratios were significantly lower in NASH than in simple steatosis (P < 0.05). Moreover, liver/heart ratios were significantly correlated with NAFLD activity scores among the patients (r = ?0.413, P < 0.05). Conclusions: The present study indicates that ^99mTc‐MIBI liver scintigraphy would be a useful non‐invasive functional imaging method with which to evaluate disease activity of NAFLD and distinguish NASH from simple steatosis.     

Pre-engraftment graft-versus-host disease after allogeneic hematopoietic cell transplantation for acute leukemia

Objectives: Acute graft‐versus‐host disease (GVHD) usually occurs with neutrophil engraftment following allogeneic hematopoietic cell transplantation (HCT), but it can also occur before engraftment. We intended to analyze the effects of timing of acute GVHD on leukemia relapse and mortality. Methods: The outcomes of pre‐ and postengraftment GVHD were investigated in 384 patients who underwent allogeneic HCT for acute leukemia. Results: Acute GVHD occurred in 100 patients, pre‐engraftment in 22 and postengraftment in 78. Compared with postengraftment GVHD, pre‐engraftment GVHD was more severe, as assessed by overall grade, with more frequent and more severe skin involvement and higher incidences of non‐infectious fever, diarrhea, hepatic dysfunction, renal insufficiency, and weight gain. Compared with patients without acute GVHD, those with postengraftment GVHD had lower cumulative incidence of relapse [CIR; hazard ratio (HR), 0.470; P = 0.006] and higher cumulative incidence of non‐relapse mortality (CINRM; HR, 2.568; P < 0.001), while those with pre‐engraftment GVHD had similar CIR (HR, 0.815; P = 0.059) and higher CINRM (HR, 2.872; P = 0.036). Overall survival of patients with pre‐engraftment GVHD was lower than that of those without acute GVHD (HR, 1.976; P = 0.017), which was similar to that of those with postengraftment GVHD (HR, 0.969; P = 0.878). Separate analyses of the effects of timing of acute GVHD on post‐transplant outcomes in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) showed similar trends. Conclusion: Pre‐engraftment GVHD might be a ‘cytokine storm’ type syndrome rather than ‘real’ GVHD, indicating the need for separate analyses of pre‐ and postengraftment GVHD in future trials.     

Meaning of Low‐Density Lipoprotein‐Apheresis for Hypercholesterolemic Patients at High Risk for Recurrence of Coronary Heart Disease

Abstract: The goal of cholesterol‐lowering therapy in hypercholesterolemic patients at high risk for recurrence of coronary heart disease (CHD) is the prevention of acute coronary syndrome by stabilization of coronary atheromatous plaque. We often encounter patients in whom it is difficult to maintain the serum cholesterol level at a desirable level with dietary therapy and drug treatment, despite the development and use of statins. For secondary prevention in patients who are at high risk for the recurrence of CHD and whose cholesterol level cannot be controlled by drugs alone, low‐density lipoprotein (LDL)‐apheresis therapy, which involves removal of LDL through extracorporeal circulation, is now available. Many reports concerning improvement of vascular endothelial function, improvement of myocardial ischemia, regression of coronary atherosclerotic lesions, stabilization of coronary plaque, and reduction in the incidence of cardiac events as a result of LDL‐apheresis treatment have been published in various countries. We believe that LDL‐apheresis should be performed on hypercholesterolemic patients with existing CHD for whom diet and maximum cholesterol‐lowering drug therapies have been ineffective or not tolerated and whose LDL cholesterol level is 160 mg/dL or higher.     

Mini-BEAM and autologous hematopoietic stem-cell transplant for treatment of post-transplant lymphoproliferative disorders

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of lymphoid proliferative diseases seen as result of immunosuppression in recipients of solid organ or hematopoietic stem-cell transplantation. Options of treatment include reduction or discontinuation of immunosuppressive agents, antiviral drugs, rituximab, chemotherapy, and radiation. We report two unique cases of PTLD (CNS and plasmacytoma-like) treated successfully with salvage chemotherapy, mini-BEAM chemotherapy, and autologous stem-cell transplant. In both cases, patients were also treated with sirolimus and prednisone as immunosuppression, and neither patient rejected their solid organ transplants. With over 30 months of follow-up, both patients remain in complete remission with excellent allograft function.     

Serum markers for mitochondrial dysfunction and cell death are possible predictive indicators for drug‐induced liver injury by direct acting antivirals

Aim

We prospectively screened patients treated with direct‐acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug‐induced liver injury (DILI).

Methods

The levels of various serum markers among DILI, non‐DILI and control groups were compared. The DILI group consisted of eight patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non‐DILI group via a matched‐group design based on age, sex and disease severity. Additionally, eight healthy volunteers were employed as the controls. Serum measurements of cytokines / chemokines, cytokeratin‐18 fragment (CK‐18F) and super oxidase dismutase‐2 (SOD2) were evaluated on the date at which hepatitis C virus RNA was absent (baseline). For patients with DILI, serum measurements taken before treatment, 1 week before pronounced transaminase elevation (prominence‐1 W) and on the date at which pronounced elevation of transaminase occurred (prominence) were also evaluated.

Results

All patients treated with DAA had normalized transaminase levels at baseline. In patients with DILI, interferon‐inducible protein‐10 (IP‐10) levels were higher at prominence‐1 W than at baseline. Those patients also had significantly higher levels of SOD2 and CK‐18F at prominence‐1 W than at baseline.

Conclusion

Elevated IP‐10 may be a preconditioning chemokine for DAA‐induced liver injury, and damage markers associated with cell death and mitochondrial dysfunction are potential predictive serum markers for DILI.     

A cost-effectiveness analysis of bisoprolol for heart failure

Aims: This study considers the cost-effectiveness of bisoprolol in heart failure patients as an adjunctive therapy to usual treatment. Methods and results: A cost-effectiveness model was constructed using data available from the CIBIS I & II trials and other secondary sources. Differences in patient survival rates were calculated for bisoprolol (n=1327) and placebo groups (n=1320) extrapolating data over a 5-year period, under limited and extended benefits scenarios to calculate life years gained (LYG). Hospitalisation rates were calculated using data from both CIBIS trials. Costs were considered under two different patient management protocols for treatment initiation - shared care by outpatient clinics and GPs and initiation by a nurse working in the community. Discounted LYG were calculated to be 0.228 under the limited benefits scenario and 0.368 under the extended benefits scenario. Under the extended benefits scenario shared care resulted in a cost of pound268 per LYG or pound412 per LYG for community initiation. Under the limited benefits scenario the costs were a pound135 saving and pound69, respectively. Conclusion: This analysis has shown bisoprolol to be an economically attractive therapy in comparison with other treatments. It is hoped that its adoption by clinicians will be rapid, despite the labour intensive and time consuming up-titration process involved in its initiation.     

The impact of a specific aqua-training for adult haemophilic patients - results of the WATERCISE study (WAT-QoL)

Summary. Sport is increasingly recommended for haemophilic patients due to physical and psychological benefits. ‘WATERCISE’ is a specific aqua‐training programme for haemophiliacs in which endurance, strength, coordination and mobility are trained. In the WAT‐QoL study benefits and risks of regular WATERCISE training sessions were investigated in terms of health‐related quality of life (HRQoL), physical functioning (PF), orthopaedic joint status (OJS), bleeding frequency and factor consumption. Patients in the WATERCISE group attended an aqua‐training programme once a week for 1 h over 12 months, patients in the control group did not. Patients were matched for clinical and demographic data. Information on clinical data, orthopaedic status, PF (HEP‐Test‐Q) and HRQoL were collected in both groups at baseline and at follow‐up (6 and 12 months). Twenty‐eight adult severely affected haemophilic patients (WATERCISE group: 10 haemophilia A (HA), 3 haemophilia B (HB) patients; control group: 12 HA and 3 HB patients) were enrolled (aged 40.68 ± 12.7 years). Baseline data (body mass indices, OJS, sportive activities, HRQoL and PF) were well distributed between groups. After 12 months the WATERCISE group reported a significantly better PF (M_W = 65.22, SD = 11.3; M_C = 52.5, SD = 15.0), especially for endurance (P < 0.004). Although always differently reported by the patients within the WATERCISE group, HRQoL did not prove to be significantly different between groups. WATERCISE seems to have a positive effect on the PF of patients suffering from haemophilia. These study findings need to be further investigated in a larger study group.     

Technical tips and troubleshooting of endoscopic biliary drainage for unresectable malignant hilar biliary obstruction

Unresectable malignant hilar biliary obstruction (MHBO) occurs in various diseases, such as cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, pancreatic cancer, and lymph node metastasis of the hilum of the liver. The majority of patients with advanced MHBO are not candidates for surgical resection because of the tumor location in the hepatic hilum and adjacent areas, advanced tumor stage, or comorbidities. Therefore, these patients often have a poor prognosis in terms of survival and quality of life. Most of these patients will require non‐surgical, palliative biliary drainage. To date, various biliary drainage techniques for unresectable MHBO (UMHBO) have been reported. Of these techniques, endoscopic biliary drainage is currently considered to be the most safe and minimally invasive procedure. However, endoscopic biliary drainage for UMHBO is still not standardized regarding the optimal stent, drainage area, stenting method, and reintervention technique. Recently, towards standardization of this technique for UMHBO, clinical research and trials including randomized controlled trials have been performed. In this article, we reviewed the most important issues regarding endoscopic biliary drainage for UMHBO, focusing on prospective studies. We also described in detail the techniques and future perspectives of endoscopic biliary drainage in patients with UMHBO.     

S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial

Background: S‐adenosyl‐L‐methionine (SAM) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione, the main cellular antioxidant. Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases (ALDs). The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24‐week trial. The primary endpoints were changes in serum aminotransferase levels and liver histopathology scores, and the secondary endpoints were changes in serum levels of methionine metabolites. Methods: We randomized 37 patients with ALD to receive 1.2 g of SAM by mouth or placebo daily. Subjects were required to remain abstinent from alcohol drinking. A baseline liver biopsy was performed in 24 subjects, and a posttreatment liver biopsy was performed in 14 subjects. Results: Fasting serum SAM levels were increased over timed intervals in the SAM treatment group. The entire cohort showed an overall improvement of AST, ALT, and bilirubin levels after 24 weeks of treatment, but there were no differences between the treatment groups in any clinical or biochemical parameters nor any intra‐ or intergroup differences or changes in liver histopathology scores for steatosis, inflammation, fibrosis, and Mallory‐Denk hyaline bodies. Conclusions: Whereas abstinence improved liver function, 24 weeks of therapy with SAM was no more effective than placebo in the treatment for ALD.     

An international collaborative study to establish the WHO 1st international standard for alpha-1-antitrypsin

Background and Objectives The aim was to establish the 1st International Standard (IS) for alpha‐1‐antitrypsin (AAT) to standardise potency assignment of therapeutic products, calibrated in moles and mg active AAT in line with product labelling practice. Assigning total protein and antigen values to the IS was also investigated. Materials and Methods The active concentration of four candidate AAT preparations was determined in an international collaborative study by inhibition of trypsin (calibrated by active‐site titration). Total protein and antigen content were determined for each candidate using local methods and in‐house standards, and a common AAT preparation. The total protein content of the IS was also determined by amino acid analysis. Potency determination of recombinant and transgenic materials against the IS was investigated in a follow‐up study. Results Data analysis for potency determination indicated no statistical difference between any of the candidates, or between the results for recombinant and plasma‐derived products. Total protein content of the IS determined by amino acid analysis was consistent with the potency value. The variability in the total protein and antigen results for the other candidates was reduced when the data were recalculated relative to the IS. Conclusions Candidate C (05/162) was established by the WHO Expert Committee on Biological Standardization (ECBS) in 2006 as the WHO 1st IS for AAT with a potency of 243 nmoles (12·4 mg) active inhibitor per ampoule. In 2008, ECBS approved the IS for potency determination of recombinant material and assigned a total protein and antigen value of 12·4 mg.     

The use of generic medications for hepatitis C

Hepatitis C, hepatitis B, HIV, TB and malaria are the five major causes of infectious disease death worldwide. In a breakthrough that rivals the invention of penicillin, drugs that cure hepatitis C, with minimal side effects and high success rates, have reached the market, but, in what must be one of the greatest tragedies of modern times, these life‐saving medications are not being deployed on a mass scale. Pharmaceutical patents are gifted to private corporations by governments for the dual purposes of protecting R&D expenditure and encouraging innovation. Unfortunately the monopoly pricing power these patents provision currently lacks adequate checks and balances, is open to abuse, and is quite clearly being abused. The sort of legislative changes required to deliver on the original goals of pharmaceutical patents will take years or even decades to eventuate. Parallel importation of generic medication offers hope to the millions of patients with HCV unable to afford access to vastly overpriced originator medications. Doctors prescribing and monitoring patients taking generics can take comfort from the fact that the REDEMPTION trial results show, like the HIV generics that came before them, that HCV generics deliver robust clinical results.     

The use of biologic therapies for the management of pediatric asthma

With better understanding of the role of type 2 inflammation in allergic asthma, there has been progress made in the development of new biologic therapies targeting these specific pathways. This review will consider diagnostic criteria for using biologic therapies for pediatric asthma with special emphasis on populations that are likely to benefit the most from particular therapies. With the exception of the anti‐immunoglobulin E, omalizumab, very few studies have been published on the efficacy and safety of biologic therapies in children, particularly anti‐interleukin‐5 (IL5) and anti‐IL4/IL13 therapies. The review will highlight the scarcity of published data in pediatric‐specific populations. In addition, we will consider the cost‐effectiveness as well as potential long‐term consequences of biologic therapies in pediatric asthma.     

Quality assurance for point-of-care testing of oral anticoagulation: a large-scale evaluation of the Hemochron Junior Signature Microcoagulation System

We report the first large-scale evaluation of the Hemochron Junior Signature (HJS) Microcoagulation System for community monitoring of oral anticoagulation and establishment of a programme of internal and external quality assurance. Over 1600 HJS results, with a simultaneous venous sample for central analysis, were obtained over a 19 month period. Monitoring of an initial period of HJS results (n = 135) revealed an International Normalized Ratio (INR) over estimation (mean +1.05), with only 27% of results within 0.5 of the central laboratory INR. A correction factor was introduced which reduced the INR bias to +0.07 and improved the percentage of results within 0.5 of the central laboratory INR to 76% (n = 353). A revised correction factor was later introduced to adjust for an under estimation at higher INR values. This changed the INR bias to -0.05, with 76% of results within 0.5 of the central laboratory INR (n = 1174). Local external quality assurance samples were distributed monthly with a total of 791 samples during the study period. 84% of test results were within 15% of the median value (range 73-97% per month). These results emphasize the value of a robust quality assurance programme when using point-of-care devices for community monitoring of oral anticoagulation.