A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA

Background & Aims: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. Methods: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5x upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. Results: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p>0.05). The proportion of patients with ALP = 15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p Conclusion: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. Lay summary: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.Peer reviewe

Survival after chemotherapy and/or radiotherapy versus self-expanding metal stent insertion in the setting of inoperable esophageal cancer: a case-control study

<p>Abstract</p> <p>Background</p> <p>Our aim was to compare survival of the various treatment modality groups of chemotherapy and/or radiotherapy in relation to SEMS (self-expanding metal stents) in a retrospective case-control study. We have made the hypothesis that the administration of combined chemoradiotherapy improves survival in inoperable esophageal cancer patients.</p> <p>Methods</p> <p>All patients were confirmed histologically as having surgically non- resectable esophageal carcinoma. Included were patients with squamous cell carcinoma, undifferentiated carcinoma as well as Siewert type I--but not type II - esophagogastric junctional adenocarcinoma. The decision to proceed with palliative treatments was taken within the context of a multidisciplinary team meeting and full expert review based on patient's wish, co-morbid disease, clinical metastases, distant metastases, M1 nodal metastases, T4-tumor airway, aorta, main stem bronchi, cardiac invasion, and peritoneal disease. Patients not fit enough to tolerate a radical course of definitive chemo- and/or radiation therapy were referred for self-expanding metal stent insertion. Our approach to deal with potential confounders was to match subjects according to their clinical characteristics (contraindications for surgery) and tumor stage according to diagnostic work-up in four groups: SEMS group (A), Chemotherapy group (B), Radiotherapy group (C), and Chemoradiotherapy group (D).</p> <p>Results</p> <p>Esophagectomy was contraindicated in 155 (35.5%) out of 437 patients presenting with esophageal cancer to the Department of General and Abdominal Surgery of the University Hospital of Mainz, Germany, between November 1997 and November 2007. There were 133 males and 22 females with a median age of 64.3 (43-88) years. Out of 155 patients, 123 were assigned to four groups: SEMS group (A) n = 26, Chemotherapy group (B) n = 12, Radiotherapy group (C) n = 23 and Chemoradiotherapy group (D) n = 62. Mean patient survival for the 4 groups was as follows: Group A: 6.92 ± 8.4 months; Group B: 7.75 ± 6.6 months; Group C: 8.56 ± 9.5 months, and Group D: 13.53 ± 14.7 months. Significant differences in overall survival were associated with tumor histology (<it>P </it>= 0.027), tumor localization (<it>P </it>= 0.019), and type of therapy (<it>P </it>= 0.005), respectively, in univariate analysis. Treatment modality (<it>P </it>= 0.043) was the only independent predictor of survival in multivariate analysis. The difference in overall survival between Group A and Group D was highly significant (<it>P </it>< 0.01) and in favor of Group D. As concerns Group D versus Group B and Group D versus Group C there was a trend towards a difference in overall survival in favor of Group D (<it>P </it>= 0.069 and <it>P </it>= 0.059, respectively).</p> <p>Conclusions</p> <p>The prognosis of inoperable esophageal cancer seems to be highly dependent on the suitability of the induction of patient-specific therapeutic measures and is significantly better, when chemoradiotherapy is applied.</p

norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis

Background & Aim: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C-23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. Methods: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. Results: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500 mg/d groups (p = 0.029, tively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary end-points, such as ALT, AST, gamma-GT, or the rate of patients achieving ALP levels <1.5 x ULN. Serious adverse events occurred in seven patients in the 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. Conclusions: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V.Peer reviewe

Assessment tool for economic and environmental valuation of temporary storage of rock masses in Swedish cities

Vid byggnation i storstadsmiljöer används ofta material som förvarats eller utvinns långt ifrån byggnadsplatsen. Materialet transporteras långa sträckor och transporten antas utgöra en stor kostnad, både ekonomiskt och miljömässigt. Överblivna jord- och bergmassor i samband med byggnation och rivning används oftast inte optimalt och återvinns sällan på bästa sätt. Genom en förbättrad hantering och återvinning av dessa jord- och bergmassor skulle involverade aktörer potentiellt kunna minska sina kostnader, samtidigt som samhället skulle kunna dra nytta av en mindre miljöpåverkan. De frågeställningar som valdes att undersöka är: Leder ett införande av mer lokala upplag för jord- och bergmassor vid byggnation i städer till en samhällsekonomisk besparing? Hur stor påverkan har miljömässiga kostnader på totalkostnaden och finns det sociala aspekter som bör beaktas? Vad finns det för möjligheter och svårigheter med att kombinera analysverktygen CBA och LCA för att värdera den samhällsekonomiska nyttan av ett lokalt upplag?  För att undersöka om ett temporärt upplag minskar kostnaderna och miljöpåverkan, har ett beräkningsverktyg utvecklats. Teorier om livscykelanalys (LCA) samt kostnad-nytta-analys (CBA) har studerats och varit grund för beräkningsverktyget. Verktyget har testats i en fallstudie i Göteborgs stad och blivit avgränsat till att endast hantera entreprenadberg. I fallstudien blev totalkostnaderna för det lokala upplaget jämfört med normalfallet relativt lika, medan de totala miljöutsläppen för det lokala upplaget blev högre. Detta beror framförallt på att en mobil kross användes i det lokala upplaget. Om istället en stationär kross kan användas i det lokala upplaget, skulle det resultatet blivit mer samhällsekonomiskt fördelaktigt. Avståndsdifferensen mellan normalfallet och fallet med ett lokalt upplag var relativt liten och detta var även en bidragande orsak till de marginella kostnadsskillnaderna. Resultatet blev att denna studie inte kan svara på om ett införande av mer lokala upplag alltid leder till en samhällsekonomisk förbättring. Beräkningsverktyget som utvecklats kan användas för att testa olika scenarion mot varandra och det kan därmed i ett tidigt stadie, ge en indikation på om implementeringen av ett lokalt upplag är samhällsekonomiskt fördelaktig. Indata till beräkningsverktyget kan enkelt ändras för att passa olika scenarion och förhållanden. Verktyget kan därför även utvecklas för mer precisa beräkningar. Beräkningsverktyget tar hänsyn till skillnader i anläggningskostnad, kostnad för krossning, transportkostnader samt miljöpåverkan. De miljömässiga och sociala kostnaderna som undersökts verkar ha liten påverkan på totalkostnaden. Undantag är dock bullerkostnaden från krossning som blir hög utan bullerskydd. Det är fördelaktigt att studera både LCA samt CBA för att få fler infallsvinklar vid bedömning och värdering av den gällande situationen jämfört med framtida förändringar.When constructing in urban areas, it is common to use material that is stored or extracted far away from the construction site. The material is then transported long distances and the transportations lead to large costs, both economically and environmentally. Excavated soil and rock masses from construction and demolition is seldom used optimally and is rarely recycled in an optimal way. An improved handling and recycling of the masses could potentially reduce costs for involved actors, while society could benefit from less environmental impact. The research questions addressed in this report are: Does the introduction of more local storage for excavated soil and rock masses for construction in cities lead to socioeconomic savings? What impact has environmental costs on the total cost, and are there social aspects that should be considered? What are the opportunities and difficulties of combining LCA and CBA to evaluate the socioeconomic benefits of a local storage? A calculation tool was developed to investigate whether a temporary storage reduces the costs and environmental impacts. Theories about Life Cycle Assessment (LCA) and Cost-benefit analysis (CBA) has been studied and been the basis for the calculation tool. The calculation tool was then tested on a realistic scenario in the city of Gothenburg and was limited to only handle excavated rock. The result was that the study could not show that an introduction of a more local storage always leads to economic improvements. A mobile crusher was used in the local storage in the tested scenario. If a stationary crusher would be used instead, the outcome would be much more beneficial with a local storage. The developed calculation tool can be adapted for testing different scenario studies and can in an early stage, give an indication for if implementing a local storage is socioeconomic beneficial. The input data can easily be changed to suit different circumstances and to make accurate calculations for different scenarios. The calculation tool takes into account differences in the cost of construction of the storage, cost of crushing rock, transport costs and environmental impact. The environmental and social costs examined seem to have little impact on the total cost. It is advantageous to study both LCA and CBA to get more perspectives in the assessment and evaluation of the current situation compared to future changes

Representation of the Swedish transport and logistics system in Samgods v. 1.1.

The national model for freight transportation in Sweden is called Samgods. The purpose of the model is to provide a tool for forecasting and planning of the transport system. Samgods can be used in policy analysis such as studying the effects of a tax change or a change in transport regulation etc. The aim of this report is to give an overview of how the Swedish transport and logistics system is represented in the Samgods model. Samgods consists of several parts, where the logistics module is the core of the model system. This report describes the setup data needed to run version 1.1 of the Samgods model. The 35 commodity groups used in the model are based on the 24 groups in the European NST/R- nomenclature. Some commodities are further divided due to their importance for Swedish freight transport and varying logistic properties. Transport demand is described with commodity specific demand matrices for 464 administrative zones inside and outside Sweden. The commodity specific P, C or W zones are split into sub-cells that include firms. The method used to generate the firm to firm flows is to divide the firms at the origin zone and destination zone into three categories according to size. A range of vehicle and vessel types are used to reflect scale advantages in transporting operations, including loading and unloading. The Samgods model uses six vehicle types for road, 10 for rail, 22 for sea and one for air. In total, 98 pre-defined transport chains are used. Infrastructure networks are used to generate the level of service (LOS)-matrix data for each vehicle/vessel type providing transport time and, distance and network related infrastructure charges. The logistics costs consist of transport costs (vehicle type specific link costs and node costs) and non-transport costs (commodity specific order costs, storage costs and capital costs in inventory as well as capital costs in transit). For each commodity it is assumed that either the overall logistics costs are optimized or the transport costs are minimized. The model generates a huge amount of output at different levels. All the output files generated are described in the last chapter of this report.Samgodstjänster Trafikverke

Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis

Background & Aims Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation

Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis

Background & Aims: Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods: Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results: The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions: Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation