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Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84–1.29], p = 0.711 and HR 1.18 [0.95–1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79–1.17], p = 0.67 and HR 1.48 [1.16–1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02–1.74], p = 0.037) and OS (HR 1.26 [1.03–1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3–3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62–3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55–5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02–1.37], p = 0.031) but not OS (HR 1.05 [0.91–1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding:Cambridge Hepatopancreatobiliary Department Research Fund.

The presented work illustrates the synthesis of a nonlinear model-based observer for the longitudinal dynamics estimation of a wheelset. This approach offers some significant improvements, such as an enhanced adherence to prescribed brake distances and an advanced usability of the condition-based maintenance of brake systems. The investigation of a single wheelset in a test rig environment enables, for example, the usage of an extended set of sensors to reliably validate the observers. The presented observer design process covers three main steps: identification of the characteristic system disturbances, implementation of the nonlinear observer dynamics, and parametrization of the observer via multicase optimization. With regard to the longitudinal dynamics, the variations of the friction conditions in the wheel–rail interface and in the interface between brake pads and brake disc have a crucial influence. Therefore, a parameter estimator and a disturbance observer are implemented, since these methods allow for a specific consideration of these disturbances. The obtained results prove that the observers accurately estimate the system behavior and provide reliable information on the longitudinal dynamics.

CTLA4Ig has been shown to improve kidney allograft function, but an increased frequency of early rejection episodes poses a major obstacle for more widespread clinical use. The deleterious effect of CTLA4Ig on Treg numbers provides a possible explanation for graft injury. Therefore, we aimed at improving CTLA4Ig's efficacy by therapeutically increasing the number of Tregs. Murine cardiac allograft transplantation (BALB/c to B6) was performed under CTLA4Ig therapy modeled after the clinically approved dosing regimen and Tregs were transferred early or late after transplant. Neither early nor late Treg transfer prolonged allograft survival. Transferred Tregs were traceable in various lymphoid compartments but only modestly increased overall Treg numbers. Next, we augmented Treg numbers in vivo by means of IL2 complexes. A short course of IL2/anti-IL2-complexes administered before transplantation reversed the CTLA4Ig-mediated decline in Tregs. Of note, the addition of IL2/anti-IL2-complexes to CTLA4Ig therapy substantially prolonged heart allograft survival and significantly improved graft histology on day 100. The depletion of Tregs abrogated this effect and resulted in a significantly diminished allograft survival. The increase in Treg numbers upon IL2 treatment was associated with a decreased expression of B7 on dendritic cells. These results demonstrate that therapy with IL2 complexes improves the efficacy of CTLA4Ig by counterbalancing its unfavorable effect on Tregs.

The “Next Generation Train” (NGT) is a double-deck high speed train concept in light-weight design that has been established as a technical and project framework in which the German Aerospace Center gathers its long-term railway vehicle research. To reduce wheel and rail wear and to enhance the passenger capacity, a mechatronic running gear with independently rotating wheels (IRW) is a key vehicle component under research. This running gear requires an advanced control of the lateral dynamics in order to fully exploit its potential in minimizing wear and noise, but this relies on information on its lateral position relative to the track. In daily railway operation it is difficult to directly measure this displacement of the wheel-pair. However, according to previous work it is possible to design an appropriate observer to estimate the lateral position, but its estimation accuracy highly depends on the chosen sensor configuration. Nevertheless, it was shown that the lateral dynamics of the running were not completely reproduced by the system description especially at suddenly changing directions in the movement of the IRW. In this work the system description is complemented by a nonlinear description of the wheel–rail geometry. Therefore, an observability analysis and an observer synthesis to estimate the lateral position for the nonlinear system of the 1:5 scaled hardware running gear is carried out. For validation purposes an extended Kalman filter with the U-D formalism is implemented at the real-time environment of the testbed and the estimation accuracy of the observer configurations is compared.

Hypervitaminosis D is a rare reason for hypercalcemia and associated with acute kidney injury. We report on two cases of hypercalcemia and acute kidney injury because of vitamin D intoxication successfully treated with denosumab. Case 1 is an 83-year-old woman, who was initially treated for 2 weeks with intravenous hydration, steroids and thereafter with furosemide without any effect on serum calcium levels and renal function. Because acute renal failure discouraged us to use intravenous bisphosphonate therapy, we applicated 60 mg denusomab subcutaneously. This led to a prompt reduction in serum calcium levels and improvement of renal function within 1 week. Case 2 is a 45-year-old athletic woman, who refused the standard therapy of steroids and forced diuresis for vitamin D intoxication. After 1 day of rehydration therapy, she received 60 mg denusomab. Similar to case 1 serum calcium declined and renal function improved within 7 days.

This chapter analyzes the transitions to adulthood of young university graduates in Morocco, more precisely, activists of the unemployed graduates movement. Their protests offer a case in point to shed light on how youth transitions in the region are institutionalized and brokered. Based on particpant observation and life story interviews, this chapter applies a ‘youth transitions regime’ perspective in order to highlight he political dimension of youth transitions. How is the structure of these transitions and the hegemonic cultural definitions of ‘youth’ and ‘adulthood’ implicit in them linked to class, gender, social exclusion and precariousness? Has the ‘Arab Spring’ impacted the Moroccan youth transitions regime and the strategies of the unemployed graduates?

Background No data concerning the prevalence and risk factors of dyskalemia in acute kidney injury (AKI) exist. We investigated (a) prevalence rates, (b) risk factors and (c) outcome of hypo- and hyperkalemia in emergency patients. Methods In this cross-sectional analysis, all patients admitted to the emergency department of a large public hospital in Switzerland between January 1st 2017 and December 31st 2018 with measurements of creatinine and potassium were included. Baseline characteristics, medication and laboratory data were extracted. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract their baseline creatinine. For all other patients, the ADQI backformula was used in order to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of hyperkalemia and outcome. Results AKI was found in 8% of patients. Hyperkalemia was present in 13% and hypokalemia in 11% of patients with AKI. AKI stage, potassium-sparing diuretics, ACE inhibitors and underlying CKD were the strongest risk factors for hyperkalemia. Hyperkalemia as well as profound hypokalemia were independently associated with prolonged length of stay and in-hospital mortality. The study is limited by its dependency on chart review data in order to identify patients with chronic kidney disease and by limitations of the ADQI backformula to calculate baseline creatinine. Conclusions Dyskalemias are common in emergency patients with AKI and are independent risk factors for adverse outcomes. Potassium-sparing diuretics, ACE-inhibitors, AKIN stage and CKD are predictors of hyperkalemia in AKI.

Background The value of liver resection (LR) for metachronous pancreatic ductal adenocarcinoma (PDAC) metastases remains controversial. However, in light of increasing safety of liver resections, surgery might be a valuable option for metastasized PDAC in selected patients. Methods We performed a retrospective, multicenter study including patients undergoing hepatectomy for metachronous PDAC liver metastases between 2004 and 2015 to analyze postoperative outcome and overall survival. All patients were operated with curative intent. Patients with oligometastatic metachronous liver metastasis with definitive chemotherapy (n = 8) served as controls. Results Overall 25 patients in seven centers were included in this study. The median age at the time of LR was 63.8 years (56.9–69.9) and the median number of metastases in the liver was 1 (IQR 1–2). There were eight non-anatomical resections (32%), 15 anatomical minor (60%) and 2 major LR (8%). Postoperative complications occurred in eleven patients (eight Clavien-Dindo grade I complications (32%) and three grade IIIa complications (12%), respectively). The 30-day mortality was 0%. The median length of stay was 8.6 days (IQR 5–11). Median overall survival following LR was 36.8 months compared to 9.2 months in patients with metachronous liver metastasis with chemotherapy (p = 0007). Discussion Liver resection for metachronous PDAC metastasis is safe and feasible in selected patients. To address general applicability and to find factors for patient selection, larger trials are urgently warranted.

Background The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. Material and methods To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 μg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. Results N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. Conclusion This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.

In the field of longitudinal train dynamics the brake process is not only a safety critical aspect but it also determines the capacity of the rail network. Therefore, a reduction of the brake distance increases the safety level and the network capacity at the same time. However, to implement an advanced brake control set-up, the knowledge of the wheel-rail adhesion and the brake pad-disc friction is usually necessary. Since the direct measurement of these determining parameters is not reasonable due to technical and economic reasons, the present work presents an estimator framework for their online identification. To ensure a robust and reliable performance of the estimator, a generic wagon model is designed and the observability of the nonlinear system is evaluated. Furthermore, a reasonable synthesis of an extended Kalman filter is discussed that takes account of the system characteristics. In the end, the test results from a roller rig verify the accurate and robust performance of the developed estimator and confirm the great potential of such a concept in the context of mechatronic railway systems.

State observer design turned out to be crucial in several recent railway vehicles projects on active control and condition monitoring at DLR, but may also be useful for emerging technologies like the cyber physical system and the digital twin approach or the realization of predictive maintenance concepts. With this background and motivation the paper presents a process in three steps: (i) an initial analysis results in a physical model, (ii) the subsequent transfer to state space representation facilitates the prove of observability and (iii) the observer synthesis supports the design of the observer feedback law. Results from two projects, one related to longitudinal or traction dynamics, the other associated to the guidance task of independently rotating wheels, demonstrate the application of the observer design process and offers a comparison of observer estimates with measurements.

Background Open abdomen (OA) may be required in patients with abdominal trauma, sepsis or compartment syndrome. Vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) is a widely used approach for temporary abdominal closure to close the abdominal wall. However, this method is associated with a high incidence of re-operations in short term and late sequelae such as incisional hernia. The current study aims to compare the results of surgical strategies of OA with versus without permanent mesh augmentation. Methods Patients with OA treatment undergoing vacuum-assisted wound closure and an intraperitoneal onlay mesh (VAC-IPOM) implantation were compared to VAWCM with direct fascial closure which represents the current standard of care. Outcomes of patients from two tertiary referral centers that performed the different strategies for abdominal closure after OA treatment were compared in univariate and multivariate regression analysis. Results A total of 139 patients were included in the study. Of these, 50 (36.0%) patients underwent VAC-IPOM and 89 (64.0%) patients VAWCM. VAC-IPOM was associated with reduced re-operations (adjusted incidence risk ratio 0.48 per 10-person days; CI 95% = 0.39–0.58, p

To compare the value of functional future liver remnant (functFLR) to established clinical and imaging variables in prediction of post-hepatectomy liver failure (PHLF) after major liver resection. This retrospective, cross-sectional study included 62 patients, who underwent gadoxetic acid enhanced MRI and MDCT within 10 weeks prior to resection of ≥ 4 liver segments. Future liver remnant (FLR) was measured in MDCT using semi-automatic software. Relative liver enhancement for each FLR segment was calculated as the ratio of signal intensity of parenchyma before and 20 min after i.v. administration of gadoxetic acid and given as mean (remnantRLE). Established variables included indocyanine green clearance, FLR, proportion of FLR, weight-adapted FLR and remnantRLE. functFLR was calculated as FLR multiplied by remnantRLE and divided by patient’s weight. The association of measured variables and PHLF was tested with univariate and multivariate logistic regression analysis and receiver operator characteristics (ROC) curves compared with the DeLong method. Sixteen patients (25.8%) experienced PHLF. Univariate logistic regression identified FLR (p = 0.015), proportion of FLR (p = 0.004), weight-adapted FLR (p = 0.003), remnantRLE (p = 0.002) and functFLR (p = 0.002) to be significantly related to the probability of PHLF. In multivariate logistic regression analysis, a decreased functFLR was independently associated with the probability of PHLF (0.561; p = 0.002). Comparing ROC curves, functFLR showed a significantly higher area under the curve (0.904; p < 0.001) than established variables. functFLR seems to be superior to established variables in prediction of PHLF after major liver resection. • functFLR is a parameter combining volumetric and functional imaging information, derived from MDCT and gadoxetic acid enhanced MRI. • In comparison to other established methods, functFLR is superior in prediction of post-hepatectomy liver failure. • functFLR could help to improve patient selection prior major hepatic surgery.

Das Thema Hyponatriamie ist von groser klinischer Relevanz in der taglichen Praxis. Es ist als „Symptom“ vieler unterschiedlicher Organerkrankungen zu sehen. Neben endokrinologischen sind auch nephrologische, pulmologische, kardiologische, neuropsychiatrische und gastrointestinale/hepatale Ursachen von Relevanz. Zusatzlich kann auch eine inadaquate Behandlung des Wasser- und Volumenhaushalts (Infusion oder diuretische Therapie) zu einer Hyponatriamie fuhren. Aktuelle europaische bzw. amerikanische Empfehlungen zur Diagnose und Therapie der Hyponatriamie konnen die Behandlung erleichtern. Diese Richtlinien sind wertvoll fur die tagliche Praxis, konnen aber nicht alle Aspekte abdecken. Deshalb ist es wichtig, auch die physiologischen Zusammenhange in der Entstehung und Aufrechterhaltung einer Hyponatriamie zu verstehen.

Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in non-irradiated recipient mice conditioned with costimulation blockade and mTOR inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation (BMT) led to BM engraftment and persistent chimerism without Treg transfer, but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor-reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC. This article is protected by copyright. All rights reserved.

Kidney transplantation represents the treatment of choice for end-stage renal disease (ESRD). However, nephrectomy bears certain short- as well as long-term risks for the healthy, voluntary donor. As obesity is increasing and is a known risk factor for surgical complications, we wanted to assess the impact of BMI on perioperative complication rates and renal function.We retrospectively assessed patients undergoing living donor kidney nephrectomy at our institution. We identified 289 donors that underwent unilateral nephrectomy between January 2006 and December 2015. Donors were categorized according to their BMI (BMI25 kg/m126 donors (43.6%) had a BMI25 while 120 (41.5%) had a BMI ≥25/30 and 43 (14.9%) were obese with a BMI ≥30. BMI had no statistically significant influence on the percentage of laparoscopic approach (86.5% vs. 83.3% vs. 88.4%, p = 0.6564), on conversion rates (0% vs. 2.0% vs. 2.6%, p = 0.2879) or postoperative complication rates defined as Clavien Dindo ≥ II (8.7% vs. 13.3% vs. 14.0%, respectively; p = 0.4474). Notably, there were no Grade III or higher complications in any group. There was no difference in pre-operative kidney function, postoperative surgical site infection or systemic infection. BMI and male sex had a statistically significant influence on short-term decline of eGFR.Obese donors do not suffer from an increased risk of intraoperative or perioperative complication rates. However, male sex and high BMI are associated with a more pronounced short-term decline in renal function. The impact of BMI on long-term consequences for kidney donors needs to be defined in larger prospective cohorts.

Background While the number of laparoscopic liver resections (LLRs) is increasing worldwide, its impact on physical recovery remains unclear. We hypothesized that LLR is associated with better physical recovery than open liver resection (OLR). To address this question, we investigated the impact of laparoscopic liver resection compared to open liver resection on physical recovery in a prospective trial. Methods Twenty-one patients who underwent LR were included in this study (11 OLR (52.4%) and 10 LLR (47.6%), respectively). Physical recovery was measured by bicycle stress testing at months 1 and 6 after surgery and compared to preoperative stress testing. Standardized performance for bicycle stress testing was calculated based on age, sex, height and weight. Physical recovery was compared between groups as change of performance (%). Results Median age was 58 years (Inter Quartile Range (IQR): 44–68), and the main indications for LR were colorectal liver metastases (n = 10; 45%) and hepatocellular carcinoma (n = 6; 27%). The one-month change of performance level was −8% (IQR: -12-1) compared to the preoperative level with no significant difference between open and laparoscopic LR (LLR: -8% (-11 – 1); OLR: -6% (-12 – 4), p = 0.833). Furthermore, 6 months postoperatively, patients in both groups had not reached back their preoperative performance level (LLR: -5.7% (−8.4 - 18.6); OLR -4. 8% (−12.6 - 1.9), p = 0.833). Conclusion In this study, we report an impaired physical recovery after LR that was not fully restored 6 months after surgery. There was no significant difference between open and laparoscopic LR in terms of bicycle stress testing. Limitations of the study include the limited sample size and differences, albeit non-statistically significant, in the baseline characteristics of the two groups. To rule out a possible role of age or underlying indication for liver resection on physical recovery, future randomized controlled trials need to be performed.

The newly released commercial DLR RailwayDynamics Library is intended to support the design, optimization and control development as well as hardware- and software-inthe-loop testing of railway vehicles mainly on the system level. To this aim, it provides the capability to consider vehicle dynamics issues such as traction, comfort and safety in multi-domain engineering tasks by preparation of vehicle, track, wheel-rail contact models and roller rig scenarios on different levels of detail. Exploiting several precursor papers on specific railway modeling topics, their models have been collected and reorganized in order to propose a sound modeling framework dedicated to railway dynamics. The paper gives an overview on particular concepts and ideas of the library, presents several application examples and discusses two approaches to organize multi-domain modeling.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft‐versus‐host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor‐specific tolerance results in improved outcomes remains unanswered. We collected follow‐up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper‐matched living‐donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72‐99) in the tolerant cohort and 118 μmol/l (IQR 99‐143) in the control group. Mixed linear‐model showed around 29% lower average creatinine levels throughout follow‐up in the tolerant group (P, A long‐term follow‐up analysis shows stable renal graft function without immunosuppression and no graft loss in patients receiving renal transplantation after hematopoietic stem cell transplantation from the same donor.

Postoperative liver dysfunction remains a major concern following hepatic resection. In order to identify patients who are at risk of developing liver dysfunction, indocyanine green (ICG) clearance has been proposed to predict postoperative liver function. All patients who underwent liver resection at the Medical University Vienna, Austria between 2006 and 2015 with preoperative ICG clearance testing (PDR, R15) were analyzed in this study. Postoperative liver dysfunction was analyzed as defined by the International Study Group of Liver Surgery. Overall, 698 patients (male: 394 (56.4%); female: 304 (43.6%)) with a mean age of 61.3 years (SD: 12.9) were included in this study, including 313 minor liver resections (44.8%) and 385 major liver resections (55.2%). One hundred and seven patients developed postoperative liver dysfunction after liver resection (15.3%). Factors associated with liver dysfunction were: male sex (p = 0.043), major liver resection (p 5.6%. To the best of our knowledge, this is the largest study analyzing the predictive value of preoperative ICG clearance assessment in patients undergoing liver resection. ICG clearance is useful to identify patients at risk of postoperative liver dysfunction.

The German Aerospace Center bundles its railway research in the long-term project “Next Generation Train” (NGT). The NGT is a high speed train concept in light-weight design and double-deck configuration. To reduce wheel and rail wear and to enhance the passenger capacity, a mechatronic running gear with independently rotating wheels (IRW) is designed. This configuration requires an advanced control of the lateral dynamics in order to fully exploit the potential in minimizing wear and noise. In terms of a model-based control design, the controller performance highly depends on the estimated lateral position of the running gear relative to the track. In a practical environment it is difficult to directly measure this displacement of the wheel-pair. Therefore this article deals with the question which sensor configuration enables an appropriate estimation of the lateral displacement and is suitable for observer design. Hence, an observability analysis and an observer synthesis to estimate the lateral position for the nonlinear system of the 1:5 scaled hardware running gear is carried out. For validation purposes three estimators are implemented at the real-time environment of the testbed and the estimation errors of the observer configurations are compared.

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naive mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Background Several clinical risk scores for patients with colorectal liver metastases (CLM) were established in cohorts of patients undergoing liver resection (LR) without neoadjuvant chemotherapy (NAC). The purpose of the study was to evaluate the predictive values of four common risk scores in the setting of NAC and the impact of score changes during NAC. Methods Risk scores (Fong, Nordlinger, Nagashima, and Konopke) were retrospectively calculated for 336 patients undergoing LR for CLM, including 109 patients without and 227 patients with NAC. In patients with NAC, the scores were calculated before and after NAC. Results In patients without NAC (n = 109), all risk scores except the Konopke score showed a significant correlation with disease-free survival (DFS). Only the Nagashima score also was predictive for overall survival (OS). In patients with NAC (n = 227), all scores except the Konopke score were predictive for DFS and OS before and after NAC. Score changes in the Fong and the Nagashima score showed a significant correlation with DFS and OS. Conclusions Nagashima score was the most universally applicable score and predicted prognosis in all tested scenarios.

Summary Whereas liver resection for colorectal metastasis has become standard of care, hepatectomy in patients with non-colorectal metastases remains controversial, mainly due to a heterogeneous tumor biology and missing data from prospective trials. This review aims at giving an overview about the indications and limits of liver surgery in patients with an advanced disease of a non-colorectal malignancy. Even though prospective trials are largely missing, results from retrospective studies indicate a survival benefit for liver resection in selected patients. Thus, in metastasized patients, treatment strategies should be developed in a multidisciplinary tumor board including an experienced liver surgeon.

IMPORTANCE: BRAF mutations are reportedly associated with aggressive tumor biology. However, in contrast with primary colorectal cancer, the association of V600E and non-V600E BRAF mutations with survival and recurrence after resection of colorectal liver metastases (CRLM) has not been well studied. OBJECTIVE: To investigate the prognostic association of BRAF mutations with survival and recurrence independently and compared with other prognostic determinants, such as KRAS mutations. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, all patients who underwent resection for CRLM with curative intent from January 1, 2000, through December 31, 2016, at the institutions participating in the International Genetic Consortium for Colorectal Liver Metastasis and had data on BRAF and KRAS mutational status were retrospectively identified. Multivariate Cox proportional hazards regression models were used to assess long-term outcomes. INTERVENTIONS: Hepatectomy in patients with CRLM. MAIN OUTCOMES AND MEASURES: The association of V600E and non-V600E BRAF mutations with disease-free survival (DFS) and overall survival (OS). RESULTS: Of 853 patients who met inclusion criteria (510 men [59.8%] and 343 women [40.2%]; mean [SD] age, 60.2 [12.4] years), 849 were included in the study analyses. Forty-three (5.1%) had a mutated (mut) BRAF/wild-type (wt) KRAS (V600E and non-V600E) genotype; 480 (56.5%), a wtBRAF/wtKRAS genotype; and 326 (38.4%), a wtBRAF/mutKRAS genotype. Compared with the wtBRAF/wtKRAS genotype group, patients with a mutBRAF/wtKRAS genotype more frequently were female (27 [62.8%] vs 169 [35.2%]) and 65 years or older (22 [51.2%] vs 176 [36.9%]), had right-sided primary tumors (27 [62.8%] vs 83 [17.4%]), and presented with a metachronous liver metastasis (28 [64.3%] vs 229 [46.8%]). On multivariable analysis, V600E but not non-V600E BRAF mutation was associated with worse OS (hazard ratio [HR], 2.76; 95% CI, 1.74-4.37; P