The efficacy and safety of dual‐therapy regimens of twice‐daily tacrolimus (BID; Prograf) and once‐daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were ...compared in a multicenter, 1:1‐randomized, two‐arm, parallel‐group study in 475 primary liver transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy‐proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per‐protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval −7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve‐month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID.
Once‐daily, prolonged‐release tacrolimus demonstrates therapeutic equivalence and comparable safety profile to established twice‐daily tacrolimus in liver transplant recipients in this randomized, double‐blind, double‐dummy study.
Conventional criteria for liver transplantation for patients with hepatocellular carcinoma are single HCC ≤ 5 cm or less than or equal to three HCCs ≤ 3 cm. We prospectively evaluated the possibility ...of slightly extending these criteria in a down‐staging protocol, which included patients initially outside conventional criteria: single HCC 5–6 cm or two HCCs ≤ 5 cm or less than six HCCs ≤ 4 cm and sum diameter ≤ 12 cm, but within Milan criteria in the active tumors after the down‐staging procedures. The outcome of patients down‐staged was compared to that of Milan criteria after liver transplantation and since the first evaluation according to an intention‐to‐treat principle. From 2003 to 2006, 177 patients with HCC were considered for transplantation: the transplantation rate was comparable between the Milan and down‐staging groups: 88/129 cases (68%) versus 32/48 cases (67%), respectively. At a median follow‐up of 2.5 years after transplantation, the 1 and 3 years' disease‐free survival rates were comparable: 80% and 71% in the Milan group versus 78% and 71% in the down‐staging. The actuarial intention‐to‐treat survival was 27/48 patients (56.3%) in the down‐staging and 81/129 cases (62.8%) in the Milan group, p = n.s. The proposed down‐staging criteria provide a comparable outcome to the conventional criteria.
This study of a new down‐staging protocol for patients with HCC moderately beyond the Milan criteria on waiting list for liver transplantation shows that both the intention‐to‐treat analysis and the post‐operative outcome were comparable between down‐staging and conventional criteria group. See also editorial by Lo in this issue on page 2485.
Since Italian liver allocation policy was last revised (in 2012), relevant critical issues and conceptual advances have emerged, calling for significant improvements. We report the results of a ...national consensus conference process, promoted by the Italian College of Liver Transplant Surgeons (for the Italian Society for Organ Transplantation) and the Italian Association for the Study of the Liver, to review the best indicators for orienting organ allocation policies based on principles of urgency, utility, and transplant benefit in the light of current scientific evidence. MELD exceptions and hepatocellular carcinoma were analyzed to construct a transplantation priority algorithm, given the inequity of a purely MELD‐based system for governing organ allocation. Working groups of transplant surgeons and hepatologists prepared a list of statements for each topic, scoring their quality of evidence and strength of recommendation using the Centers for Disease Control grading system. A jury of Italian transplant surgeons, hepatologists, intensivists, infectious disease specialists, epidemiologists, representatives of patients’ associations and organ‐sharing organizations, transplant coordinators, and ethicists voted on and validated the proposed statements. After carefully reviewing the statements, a critical proposal for revising Italy's current liver allocation policy was prepared jointly by transplant surgeons and hepatologists.
The authors present a critical proposal for the implementation of the current liver allocation policy in Italy developed following the results of a national Consensus Conference process aimed to revise, on the basis of scientific evidence, the best indicators for guiding organ allocation policies in the urgency, utility, and benefit models. See the editorial from Berg on page 2537.
Abstract Background Few papers deal with pathologic characteristics and outcome of the 3 different cholangiocarcinomas based on location (intrahepatic, peri-hilar, distal). There is little evidence ...regarding similarity and differences. Patients and Methods From two tertiary referral Italian Centers (in Bologna and Verona), 479 patients with cholangiocarcinoma were evaluated between 1980 and 2011. Several pathologic characteristics and their impact on survival were analyzed among resected patients for cholangiocarcinomas depending on the site of origin. Results Tumour location was intrahepatic in 172 cases (36%), peri-hilar in 243 (51) and distal in 64(13%). Curative resection was performed in 339 (70%) patients. Intrahepatic cholangiocarcinoma showed higher probability to achieve R0 resection (81%), but was more frequently associated with presence of microvascular invasion (71%). Distal cholangiocarcinoma presented less R0 resections (58%), higher lymphnode involvement (60%) and lower microvascular invasion (49%). Hilar cholangiocarcinoma had intermediate characteristics (R0: 65% of cases). Median follow up was 30.2 ± 38 months; the 5 years overall survival was 31% in the resected population. Overall survival curves were similar among the three groups. At univariate analysis surgical margins, lymphnode status, perineural invasion, T category, TNM stage, microvascular invasion, tumour grading had significant impact on survival. At multivariate analysis, only microvascular invasion was significantly related to long term results (HR = 1,7; 95% CI = 1,0–2,5)”. Conclusion Micro-vascular invasion has the strongest impact on survival in all three types of cholangiocarcinoma. In case of comparable pathologic characteristics and stage, the three tumors show similar outcome; depending on location, it shows a different tendency to invade bordering structures which affect the outcome.
We consider the general Landau-Lifshitz-Gilbert theory underlying the magnetization dynamics of a macrospin magnet subject to spin-torque effects and thermal fluctuations. Thermally activated ...dynamical properties are analyzed by averaging the full magnetization equations over constant-energy orbits. After averaging, all the relevant dynamical scenarios are a function of the ratio between hard and easy axis anisotropies. We derive analytically the range of currents for which limit cycles exist and discuss the regimes in which the constant energy orbit averaging technique is applicable.
Background
The benefit of surgical intervention for cancer should be estimated in relation to the life expectancy of the general population. The aim of this study was to provide a measure of relative ...survival after hepatectomy for hepatocellular carcinoma (HCC).
Methods
Consecutive patients with liver cirrhosis and HCC who underwent hepatectomy were divided into age quartiles for analysis. Short‐ and mid‐term survival rates were used to estimate survival until death for all patients, in relation to age and other co‐variables. Years of life lost (YLL) were estimated using a reference cohort, derived from the general population matched for sex, age and year of diagnosis.
Results
Some 919 patients were included in the study. The following age quartiles were identified: less than 60 years (229 patients), 60–66 years (230), 67–70 years (231) and over 70 years (229). Postoperative mortality rates were similar between age quartiles, as were survival rates up to 3 years (P = 0·404). A statistically significant reduction in 5–10‐year survival rates was observed with ageing (P = 0·001). Relative survival calculation showed that the youngest age quartile (less than 60 years) experienced the longest entire postoperative lifespan (15·6 years) but also the greatest number of YLL (11·0 years). Patients aged over 70 years had the shortest entire postoperative lifespan (6·4 years) but also the smallest number of YLL (3·7 years).
Conclusion
Although survival after liver resection for HCC is shortest in elderly patients, relative survival estimates suggest that hepatectomy can be of benefit in these patients, with a small loss of the entire individual lifespan.
Hepatectomy for HCC of benefit in elderly
We study the magnetization dynamics of spin-torque oscillators in the presence of thermal noise and as a function of the spin-polarization angle in a macrospin model. The macrospin has biaxial ...magnetic anisotropy, typical of thin film magnetic elements, with an easy axis in the film plane and a hard axis out of the plane. Using a method that averages the energy over precessional orbits, we derive analytic expressions for the current that generates and sustains out-of-plane precessional states. We find that there is a critical angle of the spin polarization necessary for the occurrence of such states and predict a hysteretic response to applied current. This model can be tested in experiments on orthogonal spin-transfer devices, which consist of both an in-plane and out-of-plane magnetized spin polarizers, effectively leading to an angle between the easy and spin-polarization axes.
Background & Aims Number-needed-to-treat is used in assessing the effectiveness of a health-care intervention, and reports the number of patients who need to be treated to prevent one additional bad ...outcome. Although largely used in medical literature, there are no studies measuring the benefit of liver transplantation (LT) over hepatic resection (HR) for hepatocellular carcinoma (HCC) in terms of “Number of patients needed to transplant (NTT).” Methods Exclusion criteria: Child-Turcotte-Pugh (CTP) Classes B–C, very large (>10 cm) and multi-nodular (>2 nodules) tumours, macroscopic vascular invasion and extra-hepatic metastases. Study population: 1028 HCC cirrhotic patients from one Eastern (n = 441) and two Western (n = 587) surgical units. Patient survival observed after HR by proportional hazard regression model was compared to that predicted after LT by the Metroticket calculator. The benefit obtainable from LT compared to resection was analysed in relationship with number of nodules (modelled as ordinal variable: single vs. oligonodular), size of largest nodule (modelled as a continuous variable), presence of microscopic vascular invasion (MVI), and time horizon from surgery (5-year vs. 10-year). Results 330 patients were beyond the Milan criteria (32%) and 597 (58%) had MVI. The prevalence of MVI was 52% in patients within Milan criteria and 71% in those beyond ( p <0.0001). In the 5-year transplant benefit analysis, nodule size and HCC number were positive predictors of transplant benefit, while MVI had a strong negative impact on NTT. Transplantation performed as an effective therapy (NTT <5) only in oligonodular HCC with largest diameter >3 cm (beyond conventional LT criteria) when MVI was absent. The 10-year scenario increased drastically the transplant benefit in all subgroups of resectable patients, and LT became an effective therapy (NTT <5) for all patients without MVI whenever tumor extension and for oligonodular HCC with MVI within conventional LT criteria. Conclusions Based on NTT analysis, the adopted time horizon (5-year vs. 10-year scenario) is the main factor influencing the benefit of LT in patients with resectable HCC and Child A cirrhosis.
We present a convenient, all-in-one framework for the scientific analysis of fully reduced, (integral-field) spectroscopic data. The Galaxy IFU Spectroscopy Tool (GIST) is entirely written in Python ...3 and conducts all the steps from the preparation of input data to the scientific analysis and to the production of publication-quality plots. In its basic set-up, it extracts stellar kinematics, performs an emission-line analysis, and derives stellar population properties from full spectral fitting and via the measurement of absorption line-strength indices by exploiting the well-known pPXF and GandALF routines, where the latter has now been implemented in Python. The pipeline is not specific to any instrument or analysis technique and provides easy means of modification and further development, thanks to its modular code architecture. An elaborate, Python-native parallelisation is implemented and tested on various machines. The software further features a dedicated visualisation routine with a sophisticated graphical user interface. This allows an easy, fully interactive plotting of all measurements, spectra, fits, and residuals, as well as star formation histories and the weight distribution of the models. The pipeline has been successfully applied to both low- and high-redshift data from MUSE, PPAK (CALIFA), and SINFONI, and to simulated data for HARMONI and WEAVE and is currently being used by the TIMER, Fornax3D, and PHANGS collaborations. We demonstrate its capabilities by applying it to MUSE TIMER observations of NGC 1433.
To investigate the impact of colonization with carbapenemase-producing Enterobacteriaceae (CPE) on the CPE infection risk after liver transplantation (LT).
Prospective cohort study of all adult ...patients undergoing LT at our centre over an 8-year period (2010–2017). Individuals were screened for CPE colonization by rectal swabs at inclusion onto the waiting list, immediately before LT and weekly after LT until hospital discharge. Asymptomatic carriers did not receive decolonization, anti-CPE prophylaxis or pre-emptive antibiotic therapy. Participants were followed up for 1 year after LT.
We analysed 553 individuals who underwent a first LT, 38 were colonized with CPE at LT and 104 acquired colonization after LT. CPE colonization rates at LT and acquired after LT increased significantly over the study period: incidence rate ratios (IRR) 1.21 (95% CI 1.05–1.39) and 1.17 (95% CI 1.07–1.27), respectively. Overall, 57 patients developed CPE infection within a median of 31 (interquartile range 11–115) days after LT, with an incidence of 3.05 cases per 10 000 LT-recipient-days and a non-significant increase over the study period (IRR 1.11, 95% CI 0.98–1.26). In multivariable analysis, CPE colonization at LT (hazard ratio (HR) 18.50, 95% CI 6.76–50.54) and CPE colonization acquired after LT (HR 16.89, 95% CI 6.95–41.00) were the strongest risk factors for CPE infection, along with combined transplant (HR 2.60, 95% CI 1.20–5.59), higher Model for End-Stage Liver Disease at the time of LT (HR 1.03, 95% CI 1.00–1.07), prolonged mechanical ventilation (HR 2.63, 95% CI 1.48–4.67), re-intervention (HR 2.16, 95% CI 1.21–3.84) and rejection (HR 2.81, 95% CI 1.52–5.21).
CPE colonization at LT or acquired after LT were the strongest predictors of CPE infection. Prevention strategies focused on LT candidates and recipients colonized with CPE should be investigated.
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