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Christina Alexa Mosk,1 Jeroen LA van Vugt,2 Huub de Jonge,1 Carlijn DM Witjes,2 Stefan Buettner,2 Jan NM Ijzermans,2 Lijckle van der Laan11Department of Surgery, Amphia Hospital, Breda, the Netherlands; 2Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the NetherlandsBackground: Both low skeletal muscle mass (LSMM) and delirium are frequently seen in elderly patients. This study aimed to investigate the association between preoperative LSMM and postoperative delirium (POD) in elderly patients undergoing colorectal cancer (CRC) surgery and to design a model to predict POD. Patients and methods: This is a retrospective observational cohort study. Patients aged 70 years or older undergoing CRC surgery from January 2013 to October 2015 were included in this study. The cross-sectional skeletal muscle area at the level of the third lumbar vertebra using computed tomography was adjusted for patients’ height, resulting in the skeletal muscle index. The lowest quartile per sex was defined as LSMM. Short Nutritional Assessment Questionnaire for Residential Care and KATZ-Activities of Daily Living were used to define malnourishment and physical dependency, respectively. POD was diagnosed using the Delirium Observational Screening Scale and geriatricians’ notes. Results: Median age of the 251 included patients was 76 years (IQR, 73–80 years), of whom 56% of patients were males, 24% malnourished, and 15% physically impaired. LSMM and POD were diagnosed in 65 and 33 (13%) patients, respectively. POD occurred significantly more in patients with LSMM (25%) compared with patients without LSMM (10%), P=0.006. In the multivariate analysis, age, history of delirium, and LSMM were significantly associated with POD. In addition, this effect increased in patients with LSMM and malnourishment (P=0.019) or physical dependency (P=0.017). Conclusion: Age, history of delirium, LSMM, and malnourishment or physical dependency were independently associated with POD. Our nomogram could be used to identify patients at an increased risk for delirium. These patients may benefit from intensive monitoring to prevent POD.Keywords: skeletal muscle mass, sarcopenia, colorectal surgery, postoperative delirium, elderly, nomogram

Pneumoperitoneum (PP), as used for laparoscopic procedures, impairs stroke volume, renal blood flow, glomerular filtration rate and urine output. This study investigated whether perioperative fluid management can abolish these negative effects of PP on hemodynamics. Twenty-one patients undergoing laparoscopic donor nephrectomy (LDN) were randomized into three groups: group 1 received overnight infusion and received a bolus of colloid before induction of anesthesia, followed by a bolus just before PP; group 2 received overnight infusion and a colloid bolus before anesthesia; group 3 served as controls and received only infusion during operation. All three groups received the same total amount of crystalloids and colloids until nephrectomy. Data analysis of the donor included; mean arterial pressure (MAP), stroke volume (SV), left ventricular ejection time (LVETc), perioperative urine output and renal function measured as the creatinine clearance (CrCl) until one-year post-operative. SV was significantly higher in group 1 compared to controls for all measurements. In the control group SV significantly decreased after changing from the supine to lateral position whereas there was no change in SV in both pre-hydrated groups. In all groups, MAP decreased after induction of anesthesia, and restored to pre-anesthetic values during PP. CrCl decreased in the control group during PP, but not in the other groups. From two days postoperative, CrCl was comparable between the three study groups. Overnight infusion and a bolus of colloid just before PP attenuate hemodynamic compromise from PP. [ABSTRACT FROM AUTHOR]

Introduction: We studied whether the choice of timing of discussing organ donation for the first time with the relatives of a patient with catastrophic brain injury in The Netherlands has changed over time and explored its possible consequences. Second, we investigated how thorough the process of brain death determination was over time by studying the number of medical specialists involved. And we studied the possible influence of the Donor Register on the consent rate.Methods: We performed a retrospective chart review of all effectuated brain dead organ donors between 1987 and 2009 in one Dutch university hospital with a large neurosurgical serving area.Results: A total of 271 medical charts were collected, of which 228 brain dead patients were included. In the first period, organ donation was discussed for the first time after brain death determination (87%). In 13% of the cases, the issue of organ donation was raised before the first EEG. After 1998, we observed a shift in this practice. Discussing organ donation for the first time after brain death determination occurred in only 18% of the cases. In 58% of the cases, the issue of organ donation was discussed before the first EEG but after confirming the absence of all brain stem reflexes, and in 24% of the cases, the issue of organ donation was discussed after the prognosis was deemed catastrophic but before a neurologist or neurosurgeon assessed and determined the absence of all brain stem reflexes as required by the Dutch brain death determination protocol.Conclusions: The phases in the process of brain death determination and the time at which organ donation is first discussed with relatives have changed over time. Possible causes of this change are the introduction of the Donor Register, the reintroduction of donation after circulatory death and other logistical factors. It is unclear whether the observed shift contributed to the high refusal rate in The Netherlands and the increase in family refusal in our hospital in the second studied period. Taking published literature on this subject into account, it is possible that this may have a counterproductive effect. [ABSTRACT FROM AUTHOR]

Background: Transplantation is the only treatment offering long-term benefit to patients with chronic kidney failure. Live donor nephrectomy is performed on healthy individuals who do not receive direct therapeutic benefit of the procedure themselves. In order to guarantee the donor's safety, it is important to optimise the surgical approach. Recently we demonstrated the benefit of laparoscopic nephrectomy experienced by the donor. However, this method is characterised by higher in hospital costs, longer operating times and it requires a well-trained surgeon. The hand-assisted retroperitoneoscopic technique may be an alternative to a complete laparoscopic, transperitoneal approach. The peritoneum remains intact and the risk of visceral injuries is reduced. Hand-assistance results in a faster procedure and a significantly reduced operating time. The feasibility of this method has been demonstrated recently, but as to date there are no data available advocating the use of one technique above the other.Methods/design: The HARP-trial is a multi-centre randomised controlled, single-blind trial. The study compares the hand-assisted retroperitoneoscopic approach with standard laparoscopic donor nephrectomy. The objective is to determine the best approach for live donor nephrectomy to optimise donor's safety and comfort while reducing donation related costs.Discussion: This study will contribute to the evidence on any benefits of hand-assisted retroperitoneoscopic versus standard laparoscopic donor nephrectomy.Trial Registration: Dutch Trial Register NTR1433. [ABSTRACT FROM AUTHOR]

The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018. Patients treated with and without adjuvant chemotherapy were matched based on tumor location, T- and N-stage (n = 522). Tumor material was available for 464 patients, with successful RNA extraction and CMS subtyping achieved in 390 patients (surgery alone group: 192, adjuvant chemotherapy group: 198). In the overall cohort, CMS4 was associated with poorest prognosis (HR 1.55; p = .03). Multivariate analysis revealed favorable RFS for the adjuvant chemotherapy group in CMS1, CMS2, and CMS4 tumors (HR 0.19; p = .01, HR 0.27; p < .01, HR 0.19; p < .01, respectively), while no significant difference between treatment groups was observed within CMS3 (HR 0.68; p = .51). CMS subtyping in this non-randomized cohort identified patients with poor prognosis and patients who may not benefit significantly from adjuvant chemotherapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background and Aims: The DRAINAGE trial was a randomized controlled trial comparing preoperative endoscopic (EBD) and percutaneous biliary drainage (PTBD) in patients with potentially resectable, perihilar cholangiocarcinoma (pCCA). The aim of this study was to compare the long-term outcomes., Methods: Patients were randomized in four tertiary referral centers. Follow-up data were available for all included patients. Primary outcome was overall survival (OS). Secondary outcomes were readmissions, and re-interventions not including in-trial interventions., Results: A total of 54 patients were randomized; 27 in both groups. Median follow-up for both groups was 62 months (95% CI 54-70). The median OS was 13 months (95% CI 7.9-18.1) in the EBD and 7 months (95% CI 0.0-17.2) in the PTBD group (P = 0.28). Twenty (37%, n = 8 EBD vs n = 12 PTBD, P = 0.43) of 54 patients were readmitted at least once, mostly due to drainage-related complications (n = 13, 24%). Of note, 14 out of the 54 patients died within the trial. A total of 76 drainage procedures (32 EBD and 44 PTBD) were performed in 28 patients. The median number of stent or drain placements was 2 (2-4) for the EBD group and 2 (1-3) for the PTBD group (P = 0.77)., Discussion: Although this follow-up study represented a small cohort, no long-term differences in survival, readmissions, and drainage procedures for EBD and PTBD were found, even when comparing the resected and unresected group. However, this study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA, even in tertiary referral centers., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: When listing for liver transplantation, one can transplant as soon as possible or introduce a test-of-time to better select patients, as the tumor's biological behavior is observed. Knowing the degree of harm caused by time itself is essential to advise patients and decide on the maximum duration of the test-of-time. Therefore, we investigated the causal effect of waiting time on post-transplant survival for patients with hepatocellular carcinoma., Methods: We analyzed the UNOS-OPTN dataset and exploited a natural experiment created by blood groups. Relations between variables and assumptions were described in a causal graph. Selection bias was addressed by inverse probability weighting. Confounding was avoided using instrumental variable analysis, with an additive hazards model in the second stage. The causal effect was evaluated by estimating the difference in 5-year overall survival if all patients waited 2 months instead of 12 months. Upper bounds of the test-of-time were evaluated for probable scenarios by means of simulation., Results: The F-statistic of the first stage was 86.3. The effect of waiting 12 months vs. 2 months corresponded with a drop in overall survival rate of 5.07% (95% CI 0.277-9.69) and 8.33% (95% CI 0.47-15.60) at 5- and 10-years post-transplant, respectively. The median survival dropped by 3.41 years from 16.21 years (95% CI 15.98-16.60) for those waiting 2 months to 12.80 years (95% CI 10.72-15.90) for those waiting 12 months., Conclusions: From a patient's perspective, the choice between ablate-and-wait vs. immediate transplantation is in favor of immediate transplantation. From a policy perspective, the extra waiting time can be used to increase the utility of scarce donor livers. However, the duration of the test-of-time is bounded, and it likely should not exceed 8 months., Impact and Implications: When listing patients with liver cancer for transplantation, it is unclear whether a test-of-time or immediate transplantation offer better outcomes at the population level. In this study, we found that increased liver transplant waiting times are detrimental in patients with liver cancer. Furthermore, our simulation showed that a pre-operative observational period can be useful to ensure good donor liver allocation, but that its duration should not exceed 8 months., (© 2022 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).)

Background & Aims: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort., Methods: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed., Results: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors., Conclusion: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality., Lay Summary: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11 th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe., Competing Interests: Conflict of interest AF declares lecture fees (from Bayer HealthCare, Gilead, Roche, MSD and Boston Scientific), and consultancy fees (from Bayer HealthCare, AstraZeneca, Roche, Guerbert, SIRTEX and Exact Science). AL reported travel and educational support (from Ipsen, Pfizer, Bayer, Advanced Acceletaro Applications, SirtEx, Novartis, Mylan and Delcath), speaker honoraria (from Merck, Pfizer, Ipsen, Incyte and AAA), advisory honoraria (from EISAI, Nutricia Ipsen, QED and Roche), and she is Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. ALl declares lecture fees (from Intercept Pharma, Abbvie, Gilead, AlfaSigma, and MSD) and consultancy fees (from Intercept and Alfa Sigma). AL-M declares travel and educational support (from Pfizer, Roche, Sanofi, Rovi, Pharma Mar and Merck). CB declares consultancy honoraria (from Incyte). GV declares consultancy fee (from Bayer HealthCare). JBA declares consulting role (for QED Therapeutics and SEALD). JMB declares research grants (from Incyte), personal fees for lecturer (from Bayer and Intercept), and consulting role (for QED Therapeutics, Albireo Pharma and OWL Metabolomics). JWV reports personal fees (from Agios, AstraZeneca, Baxter, Genoscience Pharma, Hutchison Medipharma, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Mundipharma EDO, Mylan, QED, Servier, Sirtex, Zymeworks), and grants, personal fees and non-financial support (from NuCana). LF declares research grants (from Progetto di Ricerca Dipartimentale), honoraria (from Obesity 4C Complex Clinical Cases Contest), leadership role (for HCERES, NCN), and travel expenses (from AASLD, AISF and EASL). MP-S declares honoraria (from Roche and Servier), consulting or advisory role (for AstraZeneca) and travel expenses (from Roche, BMS and Incyte). KU declares fees for advisory role (BMS). ALC, AS, ASc, AS-L, AV, BGK, DA, FL-L, GC, GLG, HJK, JA, JI, JIE, JJGM, JK, JPJ, KE, LB, LI-S, LK, MK, MM, NJ, RB, RIRM, SB, TF, VC, VS, WH, and ZS declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We aimed to externally validate the performance of the RETREAT score in a European population., Methods: This single center retrospective cohort study enrolled all consecutive patients with HCC who underwent LT between 1989 and 2019. The performance of RETREAT was assessed in the overall population and after stratification between being within or beyond the Milan criteria based on the explant pathology report. Recurrence probabilities were estimated by using the Kaplan-Meier method and compared by log-rank test., Results: We studied 203 patients; 42 patients were beyond the Milan criteria based on explant pathology. The median follow-up was 26.8 months (IQR 7.2-60.7). Overall cumulative HCC recurrence rates were 10.6%, 21.3%, and 23.0% at 2, 5, and 10 years, with the majority of recurrences extrahepatic and at multiple sites. Higher RETREAT scores were associated with higher recurrence rates, with a 10-year recurrence rate of 60.5% in patients with RETREAT ≥ 3 ( n = 65), compared to 6.2% in those with RETREAT ≤2 ( n = 138; p < 0.001). HCC recurrence rates were even lower in patients within the Milan criteria who also had a low RETREAT score ( n = 122; 2.7% at 10 years)., Conclusion: Low RETREAT scores identify patients at low risk of HCC recurrence after LT in patients within the Milan criteria based on explant pathology.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1 + tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8 + TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8 + TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8 + T cells, as depletion of CD8 + cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8 + and CD4 + TILs from human primary cancers in vitro , whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1 + TILs. See related Spotlight by Felices and Miller, p. 1110 ., (©2021 American Association for Cancer Research.)

The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for modeling HBV infection and related tumorigenesis. We first describe a primary ex vivo HBV-infection model derived from healthy donor liver organoids after challenge with recombinant virus or HBV-infected patient serum. HBV-infected organoids produced covalently closed circular DNA (cccDNA) and HBV early antigen (HBeAg), expressed intracellular HBV RNA and proteins, and produced infectious HBV. This ex vivo HBV-infected primary differentiated hepatocyte organoid platform was amenable to drug screening for both anti-HBV activity and drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (NTCP) after lentiviral transduction were not more susceptible to HBV, suggesting the necessity for additional host factors for efficient infection. We also generated transgenic organoids harboring integrated HBV, representing a long-term culture system also suitable for viral production and the study of HBV transcription. Finally, we generated HBV-infected patient-derived liver organoids from non-tumor cirrhotic tissue of explants from liver transplant patients. Interestingly, transcriptomic analysis of patient-derived liver organoids indicated the presence of an aberrant early cancer gene signature, which clustered with the hepatocellular carcinoma (HCC) cohort on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for the development of HCC and surveillance in HBV-infected patients., Competing Interests: ED, TH, SR, FC, PM, MK, SR, AB, MV, FP, CK, HG, TK, RP, CB, JI, MH, SB, RV, HC, Lv, PH, TM No competing interests declared, (© 2021, De Crignis et al.)

Scarcity of donor organs and the increment in patients awaiting a transplant increased the use of organs from expanded criteria donors or donation after circulatory death. Due to the suboptimal outcomes of these donor organs, there is an increased interest in better preservation methods, such as ex vivo machine perfusion or abdominal regional perfusion to improve outcomes. This state-of-the-art review aims to discuss the available types of perfusion techniques, its potential benefits and the available evidence in kidney, liver and pancreas transplantation. Additionally, translational steps from animal models towards clinical studies will be described, as well as its application to clinical practice, with the focus on the Netherlands. Despite the lack of evidence from randomized controlled trials, currently available data suggest especially beneficial effects of normothermic regional perfusion on biliary complications and ischemic cholangiopathy after liver transplantation. For ex vivo machine perfusion in kidney transplantation, hypothermic machine perfusion has proven to be beneficial over static cold storage in a randomized controlled trial, while normothermic machine perfusion is currently under investigation. For ex vivo machine perfusion in liver transplantation, normothermic machine perfusion has proven to reduce discard rates and early allograft dysfunction. In response to clinical studies, hypothermic machine perfusion for deceased donor kidneys has already been implemented as standard of care in the Netherlands., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Acute kidney injury (AKI) is a frequent complication after liver transplantation. Although numerous risk factors for AKI have been identified, their cumulative impact remains unclear. Our aim was therefore to design a new model to predict post-transplant AKI., Methods: Risk analysis was performed in patients undergoing liver transplantation in two centres (n = 1230). A model to predict severe AKI was calculated, based on weight of donor and recipient risk factors in a multivariable regression analysis according to the Framingham risk-scheme., Results: Overall, 34% developed severe AKI, including 18% requiring postoperative renal replacement therapy (RRT). Five factors were identified as strongest predictors: donor and recipient BMI, DCD grafts, FFP requirements, and recipient warm ischemia time, leading to a range of 0-25 score points with an AUC of 0.70. Three risk classes were identified: low, intermediate and high-risk. Severe AKI was less frequently observed if recipients with an intermediate or high-risk were treated with a renal-sparing immunosuppression regimen (29 vs. 45%; p = 0.007)., Conclusion: The AKI Prediction Score is a new instrument to identify recipients at risk for severe post-transplant AKI. This score is readily available at end of the transplant procedure, as a tool to timely decide on the use of kidney-sparing immunosuppression and early RRT., (Copyright © 2019. Published by Elsevier Ltd.)

Aim: The aim of this systematic review and meta-analysis was to present the outcome of deceased adult liver transplantation from octogenarian (≥80 years old) donors compared to younger grafts., Methods: A systematic search was performed on six databases to identify all available original papers that report the outcome of adult recipients who underwent liver transplantation from a deceased octogenarian donor., Results: Overall, 39,034 liver transplantations from 12 studies were reported with 789 (2.02%) cases receiving grafts from octogenarian donors. Eight studies were included in the meta-analysis. There was no difference regarding the one, three, and five-year graft and patient survival between the recipients of livers <80 years old and octogenarian grafts. There were significantly more episodes of biliary complications in the recipients of octogenarian grafts (34/459; 7.4%) in comparison to the recipients of livers <80 years old (372/37074; 1.0%) (OR 0.53; 95% CI = 0.35-0.81; P 0.004; I 2  = 0%). The incidence of primary non-function, vascular complications and re-transplantation did not differ between groups., Conclusions: The short- and medium-term graft and patient survival of octogenarian liver transplantation is not inferior compared to the liver transplantation with younger grafts, however with a higher rate of biliary complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

BACKGROUND Kidney re-transplantation is a relevant option for patients who are returning to dialysis after graft failure. However, evidence is lacking to what extend a third kidney transplantation in the ipsilateral iliac fossa is safe and effective. The aim of this study was to investigate the outcomes of third kidney transplantations in the ipsilateral iliac fossa compared to first and second ipsilateral fossa kidney transplantations. MATERIAL AND METHODS There were 2074 kidneys transplanted at the Erasmus MC Rotterdam and at the University Medical Centre Groningen. Donor, recipient, and surgical data were collected. The cohort was divided into 3 groups: recipients of a first graft (I KTx; n=1744), recipients of a second graft (II KTx; n=44), and recipients of a third graft (III KTx; n=7). RESULTS Recipients from the II KTx group had a significantly higher rate of primary non-function (PNF) compared to recipients in the I KTx group and recipients in the III KTx group (4.5% versus 0.7% and 0% respectively; P=0.006). The 1-year graft survival did not differ between groups: 96% for I KTx, 91% for II KTx, and 85% for III KTx (P=0.214). The 5-year graft survival did differ significantly between groups: 89% for I KTx, 82% for II KTx, and 68% for III KTx (P=0.029). There were no differences regards hospital stay and rate of complications between groups. CONCLUSIONS Third kidney transplantation in the ipsilateral iliac fossa is feasible and viable. Short-term results are comparable to the first and the second kidney transplantation, however, long-term results are inferior but acceptable compared to dialysis.

Background: Current imaging guidelines do not specify the preferred hepatobiliary contrast agent when differentiating hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH) on MRI., Purpose: To analyze intrapatient differences in the hepatobiliary phase (HBP) after use of both gadobenate dimeglumine (Gd-BOPTA) and gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI to differentiate HCA from FNH., Study Type: Retrospective., Population: Patients who underwent both Gd-BOPTA and Gd-EOB-DTPA-enhanced MRI, including 33 patients with 82 lesions (67 HCA; 15 FNH), with a step-down reference standard of pathology, 20% regression, identical appearance to earlier biopsied lesions, and stringent imaging findings., Field Strength/sequence: 1.5T and 3T HBP of Gd-BOPTA and Gd-EOB-DTPA-enhanced MRI, precontrast fat-suppressed T 1 -weighted sequence., Assessment: Signal intensities relative to the surrounding liver in the HBP were assessed by two observers., Statistical Tests: Sensitivity and specificity of HCA diagnosis were calculated for both contrast agents. Interobserver agreement was evaluated using Cohen's kappa; differences in degree of certainty for scoring a lesion were calculated by means of the Wilcoxon signed rank test. Differences in signal intensity between Gd-BOPTA and Gd-EOB-DTPA were calculated using McNemar's test., Results: Almost perfect agreement was found between observers for scored signal intensities with both contrast agents. In 30 of the 82 lesions (37%) a difference was observed between contrast agents in the HBP, with Gd-EOB-DTPA proving correct in all but one of the discordant lesions. When distinguishing HCA from FNH, Gd-BOPTA showed a sensitivity of 46% (31/67) and a specificity of 87% (13/15), while the sensitivity and specificity of Gd-EOB-DTPA was 85% (57/67) and 100% (15/15), respectively. A risk of misclassifying HCA as FNH typically occurs for Gd-BOPTA when lesions are intrinsically hyperintense (P < 0.005)., Data Conclusion: The HBP of Gd-EOB-DTPA shows superior accuracy in ruling out HCA in comparison with Gd-BOPTA, especially when the lesion is intrinsically hyperintense on T 1 -weighted imaging., Level of Evidence: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:700-710., (© 2018 International Society for Magnetic Resonance in Medicine.)

Aim: To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and asunaprevir., Methods: The antiviral activity of daclatasvir (DCV) and asunaprevir (ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus (HCV) infection., Results: Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid (MPA) showed additive antiviral effects combined with these direct acting antivirals (DAAs). MPA induces interferon-stimulated genes (ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP synthesis., Conclusion: Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest to report.

Aim: To evaluate outcome of acute management and risk of rebleeding in patients with massive hemorrhage due to hepatocellular adenoma (HCA)., Methods: This retrospective cohort study included all consecutive patients who presented to our hospital with massive hemorrhage (grade II or III) due to ruptured HCA and were admitted for observation and/or intervention between 1999-2016. The diagnosis of HCA was based on radiological findings from contrast-enhanced magnetic resonance imaging (MRI) or pathological findings from biopsy or resection of the HCA. Hemorrhage was diagnosed based on findings from computed tomography or MRI. Medical records were reviewed for demographic features, clinical presentation, tumor features, initial and subsequent management, short- and long-term complications and patient and lesion follow-up., Results: All patients were female ( n = 23). Treatment in the acute phase consisted of embolization ( n = 9, 39.1%), conservative therapy ( n = 13, 56.5%), and other intervention ( n = 1, 4.3%). Median hemoglobin level decreased significantly more on days 0-3 in the intervention group than in the patients initially treated conservatively (0.9 mmol/L vs 2.4 mmol/L respectively, P = 0.006). In total, 4 patients suffered severe short-term complications, which included hypovolemic shock, acute liver failure and abscess formation. After a median follow-up of 36 mo, tumor regression in non-surgically treated patients occurred with a median reduction of 76 mm down to 25 mm. Four patients underwent secondary (elective) treatment ( i.e ., tumor resection) to address HCA size of > 5 cm and/or desire for future pregnancy. One case of rebleeding was documented (4.3%). None of the patients experienced long-term complication (mean follow-up time: 36 mo)., Conclusion: With a 4.3% risk of rebleeding, secondary (elective) treatment of HCA after massive hemorrhage may only be considered in patients with persistent HCA > 5 cm., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare.

BACKGROUND The Bosniak system for radiological classification of renal cysts offers a tool for surgical decision-making in clinical practice. Although 95% of Bosniak 2F cysts remain benign, a consensus on the management of Bosniak 2F cysts in kidney donation has not been developed. CASE REPORT We present a donor with a Bosniak 2F cyst, who successfully donated her kidney after partial resection of the Bosniak 2F cyst. Postoperative pathology examination of the partially resected cystic wall revealed a multilocular cystic renal cell carcinoma. Postoperative pathology examination revealed a multilocular cystic renal cell carcinoma. Resection of the Bosniak 2F cyst provides 2 advantages: the recipient receives a new donor kidney and will be free of dialysis, and the donor will be free of surveillance. CONCLUSIONS We present a practical guideline for kidney donors with Bosniak 2F cysts, balancing the risk of tumor transmission or recurrence with the benefit associated with organ transplantation, without compromising the risk of the donor and recipient. Further evaluation of this algorithm by longer follow-up and more studies is needed to prove its safety.

Introduction: The completeness of the pathological examination of resected colon cancer specimens is important for further clinical management. We reviewed the pathological reports of 356 patients regarding the five factors (pT-stage, tumor differentiation grade, lymphovascular invasion, tumor perforation and lymph node metastasis status) that are used to identify high-risk stage II colon cancers, as well as their impact on overall survival (OS)., Methods: All patients with stage II colon cancer who were included in the first five years of the MATCH study (1 July 2007 to 1 July 2012) were selected (n = 356). The hazard ratios of relevant risk factors were calculated using Cox Proportional Hazards analyses., Results: In as many as 69.1% of the pathology reports, the desired information on one or more risk factors was considered incomplete. In multivariable analysis, age (HR: 1.07, 95%CI 1.04-1.10, p < .001), moderately- (HR: 0.35, 95%CI 0.18-0.70, p = .003) and well (HR 0.11, 95%CI 0.01-0.89, p = .038) differentiated tumors were significantly associated with OS., Conclusions: Pathology reports should better describe the five high-risk factors, in order to enable proper patient selection for further treatment. Chemotherapy may be offered to stage II patients only in select instances, yet a definitive indication is still unavailable.

Objectives: The aim of this study was to evaluate the effects of 2 types of external ureteral stents on the number of urological complications after kidney transplant., Materials and Methods: Data were retrospectively collected from 366 consecutive transplants performed between January 2013 and January 2015 in our hospital, in which an external ureteral stent was placed during surgery and removed after 9 days. Urological complications were defined as urinary leakage or ureteral stenosis requiring percutaneous nephrostomy placement., Results: A total of 197 patients received a straight stent with 2 larger side holes (type A; 8F "Covidien" tube; Covidien, Dublin, Ireland) and 169 patients received a single J stent with 7 smaller side holes (type B; 7F "Teleflex" single J stent; Teleflex Medical, Athlone, Ireland). We found a significantly higher number of percutaneous nephrostomy placements with type A stents, with 34 (17%) versus 16 (9%) in type B (P = .030). Reason for percutaneous nephrostomy placement, occurrence of stent dysfunction, and need for early removal (< 8 days) were equal in both groups (P = .397), whereas incidence of rejection and urinary tract infection were higher in type B stent group. Patient and graft survival did not differ between the groups., Conclusions: Use of the type B stent was associated with less urological complications compared with the type A stent.

Background: The association between body composition (e.g. sarcopenia or visceral obesity) and treatment outcomes, such as survival, using single-slice computed tomography (CT)-based measurements has recently been studied in various patient groups. These studies have been conducted with different software programmes, each with their specific characteristics, of which the inter-observer, intra-observer, and inter-software correlation are unknown. Therefore, a comparative study was performed., Methods: Fifty abdominal CT scans were randomly selected from 50 different patients and independently assessed by two observers. Cross-sectional muscle area (CSMA, i.e. rectus abdominis, oblique and transverse abdominal muscles, paraspinal muscles, and the psoas muscle), visceral adipose tissue area (VAT), and subcutaneous adipose tissue area (SAT) were segmented by using standard Hounsfield unit ranges and computed for regions of interest. The inter-software, intra-observer, and inter-observer agreement for CSMA, VAT, and SAT measurements using FatSeg, OsiriX, ImageJ, and sliceOmatic were calculated using intra-class correlation coefficients (ICCs) and Bland-Altman analyses. Cohen's κ was calculated for the agreement of sarcopenia and visceral obesity assessment. The Jaccard similarity coefficient was used to compare the similarity and diversity of measurements., Results: Bland-Altman analyses and ICC indicated that the CSMA, VAT, and SAT measurements between the different software programmes were highly comparable (ICC 0.979-1.000, P < 0.001). All programmes adequately distinguished between the presence or absence of sarcopenia (κ = 0.88-0.96 for one observer and all κ = 1.00 for all comparisons of the other observer) and visceral obesity (all κ = 1.00). Furthermore, excellent intra-observer (ICC 0.999-1.000, P < 0.001) and inter-observer (ICC 0.998-0.999, P < 0.001) agreement for all software programmes were found. Accordingly, excellent Jaccard similarity coefficients were found for all comparisons (mean ≥ 0.964)., Conclusions: FatSeg, OsiriX, ImageJ, and sliceOmatic showed an excellent agreement for CSMA, VAT, and SAT measurements on abdominal CT scans. Furthermore, excellent inter-observer and intra-observer agreement were achieved. Therefore, results of studies using these different software programmes can reliably be compared., (© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

To establish the outcome of live kidney donors 5 years after donation, we investigated the risk for progressive renal function decline and quality of life (QoL). Data on estimated glomerular filtration rate (eGFR), creatinine, hypertension, QoL and survival were assessed in a prospective cohort of 190 donors, who donated between 2008 and 2010. Data were available for >90%. The mean age predonation was 52.8 ± 11.5 years, 30 donors having pre-existent hypertension. The mean follow-up was 5.1 ± 0.9 years. Eight donors had died due to non-donation-related causes. After 5 years, the mean eGFR was 60.2 (95% CI 58.7-62.7) ml/min/1.73 m 2 , with a median serum creatinine of 105.1 (95% CI 102.5-107.8) μmol/l. eGFR decreased to 33.6% and was longitudinally lower among men than women and declining with age (P < 0.001), without any association on QoL. Donors with pre-existent and new-onset hypertension demonstrated no progressive decline of renal function overtime compared to nonhypertensives. No donors were found with proteinuria, microalbuminuria or at risk for end-stage renal disease. After an initial decline postdonation, renal function remained unchanged overtime. Men and ageing seem to affect renal function overtime, while decreased renal function did not affect QoL. These data support further stimulation of living kidney donation programmes as seen from the perspective of donor safety., (© 2016 Steunstichting ESOT.)

Introduction: While preoperative chemotherapy (pCT) is utilized in many intra-abdominal cancers, the use of pCT among patients with intrahepatic cholangiocarcinoma (ICC) remains ill defined. As such, the objective of the current study was to examine the impact of pCT among patients undergoing curative-intent resection for ICC., Methods: Patients who underwent hepatectomy for ICC were identified from a multi-institutional international cohort. The association between pCT with peri-operative and long-term clinical outcomes was assessed., Results: Of the 1 057 patients who were identified and met the inclusion criteria, 62 patients (5.9%) received pCT. These patients were noticed to have more advanced disease. Median OS (pCT:46.9 months vs no pCT:37.4 months; P = 0.900) and DFS (pCT: 34.1 months vs no pCT: 29.1 months; P = 0.909) were similar between the two groups. In a subgroup analysis of propensity-score matched patients, there was longer OS (pCT:46.9 months vs no pCT:29.4 months) and DFS (pCT:34.1 months vs no pCT:14.0 months); however this did not reach statistical significance (both P > 0.05)., Conclusion: In conclusion, pCT utilization among patients with ICC was higher among patients with more advanced disease. Short-term post-operative outcomes were not affected by pCT use and receipt of pCT resulted in equivalent OS and DFS following curative-intent resection., (© 2017 Wiley Periodicals, Inc.)

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy arising from the liver. ICC makes up about 10% of all cholangiocarcinomas. It arises from the peripheral bile ducts within the liver parenchyma, proximal to the secondary biliary radicals. Histologically, the majority of ICCs are adenocarcinomas. Only a minority of patients (15%) present with resectable disease, with a median survival of less than 3 years. Multidisciplinary management of ICC is complicated by large differences in disease course for individual patients both across and within tumor stages. Risk models and nomograms have been developed to more accurately predict survival of individual patients based on clinical parameters. Predictive risk factors are necessary to improve patient selection for systemic treatments. Molecular differences between tumors, such as in the epidermal growth factor receptor status, are promising, but their clinical applicability should be validated. For patients with locally advanced disease, several treatment strategies are being evaluated. Both hepatic arterial infusion chemotherapy with floxuridine and yttrium-90 embolization aim to downstage locally advanced ICC. Selected patients have resectable disease after downstaging, and other patients might benefit because of postponing widespread dissemination and biliary obstruction., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Live kidney donors are exhaustively screened pre-donation, creating a cohort inherently healthier at baseline than the general population. In recent years, three renowned research groups reported unfavourable outcomes for live kidney donors post-donation that contradicted their previous studies. Here, we compared the study design and analysis of the most recent and previous studies to determine whether the different outcomes were due to methodological design or reflect a real potential disadvantage for living kidney donors. All six studies on long-term risk after live kidney donation were thoroughly screened for the selection of study population, controls, data quality, and statistical analysis. Our detailed review of the methodology revealed key differences with respect to selection of donors and compared non-donors, data quality, follow-up duration, and statistical analysis. In all studies, the comparison group of non-donors was healthier than the donors due to more extensive exclusion criteria for non-donors. Five of the studies used both restriction and matching to address potential confounding. Different matching strategies and statistical analyses were used in the more recent studies compared to previous studies and follow-up was longer. Recently published papers still face bias. Strong points compared to initial analyses are the extended follow-up time, large sample sizes and better analysis, hence increasing the reliability to estimate potential risks for living kidney donors on the long-term. Future studies should focus on equal selection criteria for donors and non-donors, and in the analysis, follow-up duration, matched sets, and low absolute risks among donors should be accounted for when choosing the statistical technique.

During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.

Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8 + lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 ( p < 0.001), Galectin-9 ( p < 0.001) and HVEM ( p < 0.001), and low CD8 + TIL count ( p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8 + TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8 + TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8 + TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

Background & Aims: Hepatocellular adenoma (HCA) is a rare benign liver tumor, which typically develops in women in their reproductive phase and is associated with the use of oral contraceptives. The aim of this study was to evaluate whether follow-up of HCA can be safely terminated after the occurrence of menopause. Secondary, we studied the impact of the diagnosis HCA on health-related quality of life (HRQoL)., Methods: This was a cross-sectional cohort study, including 48 post-menopausal women with HCA. Patients underwent ultrasound examination and the size of HCA was compared to size at the last follow-up imaging (CT, MRI or ultrasound). HRQoL was evaluated by the Liver Disease Symptom Index 2.0 and Short Form 12., Results: Median time since last follow-up was 60.5months. In 44 patients 43.5% of the lesions were undetectable, 32.6% were stable in size and 19.6% became smaller. Mean diameter of HCA was 17.2mm compared to 35.9mm at last follow-up (p<0.001). There was a positive correlation between difference in size and time since last follow-up (p<0.001). No significant effect of HCA subtype on difference in size was found. Regarding HRQoL, study patients scored significantly lower on the mental component summary score compared to the general female Dutch population., Conclusions: HCA diameter became significantly smaller after the occurrence of menopause and as time progresses, this regression increased. This suggests that routine follow-up of HCA <5cm in post-menopausal women after subsequent follow-up is not required. Notably we found that patient's mental HRQoL was inferior to that of the general population., Lay Summary: In this study we investigated if hepatocellular adenoma, a benign tumor of the liver that is found mostly in women and is associated with female hormones, regresses in size after the occurrence of menopause in female patients over 50years of age. We made an ultrasound of the liver lesion and found that the average size of the adenomas becomes significantly smaller. This could mean that female patients with a small (<5cm) hepatocellular adenoma who are post-menopausal do not have to remain in follow-up., Clinical Trial Number: MEC-2015-385., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Microthrombi formation provoked by warm ischemia and vascular stasis is thought to increase the risk of nonanastomotic strictures (NAS) in liver grafts obtained by donation after circulatory death (DCD). Therefore, potentially harmful intraoperative thrombolytic therapy has been suggested as a preventive strategy against NAS. Here, we investigated whether there is histological evidence of microthrombi formation during graft preservation or directly after reperfusion in DCD livers and the development of NAS. Liver biopsies collected at different time points during graft preservation and after reperfusion were triple-stained with hematoxylin-eosin (H & E), von Willebrand factor VIII (VWF), and Fibrin Lendrum (FL) to evaluate the presence of microthrombi. In a first series of 282 sections obtained from multiple liver segments of discarded DCD grafts, microthrombi were only present in 1%-3% of the VWF stainings, without evidence of thrombus formation in paired H & E and FL stainings. Additionally, analysis of 132 sections obtained from matched, transplanted donation after brain death and DCD grafts showed no difference in microthrombi formation (11.3% versus 3.3% respectively; P = 0.082), and no relation to the development of NAS (P = 0.73). Furthermore, no microthrombi were present in perioperative biopsies in recipients who developed early hepatic artery thrombosis. Finally, the presence of microthrombi did not differ before or after additional flushing of the graft with preservation solution. In conclusion, the results of our study derogate from the hypothesis that DCD livers have an increased tendency to form microthrombi. It weakens the explanation that microthrombi formation is a main causal factor in the development of NAS in DCD and that recipients could benefit from intraoperative thrombolytic therapy to prevent NAS following liver transplantation. Liver Transplantation 22 1676-1687 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

miRNAs have emerged as promising biomarkers because of their association with cell stress and diseases and their easy detection and stability in many body fluids. Because of the sensitivity, the method of choice to detect miRNAs is quantitative RT-PCR (RT-qPCR). Therapeutics, in particular circulating anticoagulants, are notorious for their inhibitory effect on RT-qPCR-based measurements. The effect of heparin contamination on inhibition of RT-qPCR from miRNAs isolated from urine has, however, never been investigated. We obtained urine samples from healthy controls and from heparinized patients undergoing major surgery (live kidney donation or liver transplantation) (n = 27). Samples were spiked with synthetic miRNAs to monitor RNA loss during workup, and levels of endogenous and spiked-in miRNAs were quantified by RT-qPCR. Endogenous miRNAs in urine were protected from degradation, but levels differed substantially within surgery groups. Variability in detection levels of spiked-in miRNAs was low in nonhospitalized controls, but was high in both surgery groups, and the difference in miRNA levels correlated well with the heparin concentration in urinary samples. Treatment of urinary RNA with heparinase I during RT-qPCR strongly reduced this variation in a dose-dependent manner. Heparinase I should therefore be considered as standard step for detection of miRNA in urine from hospitalized individuals., (Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Hepatocellular adenoma (HCA) is a rare, benign liver tumor. Discovery of this tumor is usually as an incidental finding, correlated with the use of oral contraceptives, or pregnancy. Treatment options have focused on conservative management for the straightforward, smaller lesions (<5 cm), with resection preferred for larger lesions (>5 cm) that pose a greater risk of hemorrhage or malignant progression. In recent years, a new molecular subclassification of HCA has been proposed, associated with characteristic morphological features and loss or increased expression of immunohistochemical markers. This subclassification could possibly provide considerable benefits in terms of patient stratification, and the selection of treatment options. In this review we discuss the decision-making processes and associated risk analyses that should be made based on lesion size, and subtype. The usefulness of this subclassification system in terms of the procedures instigated as part of the diagnostic work-up of a suspected HCA will be outlined, and suitable treatment schemes proposed., Competing Interests: The authors declare that there is no conflict of interest.

Background: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG)., Methods/design: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria., Results: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients., Conclusion: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

Background: Minimally invasive live donor nephrectomy has become a fully implemented and accepted procedure. Donors have to be well educated about all risks and details during the informed consent process. For this to be successful, more information regarding short-term outcome is necessary., Methods: A literature search was performed; all studies discussing short-term complications after minimally invasive live donor nephrectomy were included. Outcomes evaluated were intraoperative and postoperative complications, conversions, operative and warm ischemia times, blood loss, length of hospital stay, pain score, convalescence, quality of life, and costs., Results: One hundred ninety articles were included in the systematic review, 41 in the meta-analysis. Conversion rate was 1.1%. Intraoperative complication rate was 2.3%, mainly bleeding (1.5%). Postoperative complications occurred in 7.3% of donors, including infectious complications (2.6%), of which mainly wound infection (1.6%) and bleeding (1.0%). Reported mortality rate was 0.01%. All minimally invasive techniques were comparable with regard to complication or conversion rate., Conclusions: The used techniques for minimally invasive live donor nephrectomy are safe and associated with low complication rates and minimal risk of mortality. These data may be helpful to develop a standardized, donor-tailored informed consent procedure for live donor nephrectomy.

The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.

The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell-cycle dynamics and carcinogenesis., Competing Interests: Compliance with ethical standards Informed consent was obtained from all patients and the study was approved by the Ethics Committee at our institution.

Introduction: Although widely used, the 7th edition American Joint Committee on Cancer (AJCC) staging system for perihilar cholangiocarcinoma (PHC) may be limited. Disease-specific nomograms have been proposed as a better means to predict long-term survival for individual patients. We sought to externally validate a recently proposed nomogram by Memorial Sloan Kettering Cancer Center (MSKCC) for PHC, as well as identify factors to improve the prediction of prognosis for patients with PHC., Methods: Four hundred seven patients who underwent surgery for PHC between 1988 and 2014 were identified using an international, multi-center database. Standard clinicopathologic and outcome data were collected. The predictive power of the AJCC staging system and nomogram were assessed., Results: Median survival was 24.4 months; 3- and 5-year survival was 37.2 and 20.8 %, respectively. The AJCC 7th edition staging system (C-index 0.570) and the recently proposed PHC nomogram (C-index 0.587) both performed poorly. A revised nomogram based on age, lymphovascular invasion, perineural invasion, and lymph node metastases performed better (C-index 0.682). The calibration plot of the revised PHC nomogram demonstrated good calibration., Conclusion: The 7th edition AJCC staging system and the MSKCC nomogram had a poor ability to predict long-term survival for individual patients with PHC. A revised nomogram provided more accurate prediction of survival, but will need to be externally validated.

Background: CTCs are a promising alternative for metastatic tissue biopsies for use in precision medicine approaches. We investigated to what extent the molecular characteristics of circulating tumor cells (CTCs) resemble the liver metastasis and/or the primary tumor from patients with metastatic colorectal cancer (mCRC)., Results: The CTC profiles were concordant with the liver metastasis in 17/23 patients (74%) and with the primary tumor in 13 patients (57%). The CTCs better resembled the liver metastasis in 13 patients (57%), and the primary tumor in five patients (22%). The strength of the correlations was not associated with clinical parameters. Nine genes (CDH1, CDH17, CDX1, CEACAM5, FABP1, FCGBP, IGFBP3, IGFBP4, and MAPT) displayed significant differential expressions, all of which were downregulated, in CTCs compared to the tissues in the 23 patients., Patients and Methods: Patients were retrospectively selected from a prospective study. Using the CellSearch System, CTCs were enumerated and isolated just prior to liver metastasectomy. A panel of 25 CTC-specific genes was measured by RT-qPCR in matching CTCs, primary tumors, and liver metastases. Spearman correlation coefficients were calculated and considered as continuous variables with r=1 representing absolute concordance and r=-1 representing absolute discordance. A cut-off of r>0.1 was applied in order to consider profiles to be concordant., Conclusions: In the majority of the patients, CTCs reflected the molecular characteristics of metastatic cells better than the primary tumors. Genes involved in cell adhesion and epithelial-to-mesenchymal transition were downregulated in the CTCs. Our results support the use of CTC characterization as a liquid biopsy for precision medicine.

Objectives: Living donor kidney transplantation offers advantages to the patient, however involves risks to the donor. To optimize donors' mental health after donation, we studied the influence of psychological factors on this outcome. Potential predictors were based on models of Lazarus () and Ursin and Eriksen () that describe predictors of mental health mediated by stress., Design: Prospective design., Methods: Living kidney donors (n = 151) were interviewed before donation and completed questionnaires 2.5 months before and 3 and 12 months post-donation. Using multilevel regression models, we examined whether appraisals, expectations, knowledge, social support, coping, life events, and sociodemographic characteristics predicted psychological symptoms and well-being and whether these relationships were mediated by stress., Results: A greater increase in psychological symptoms over time was found among donors without a partner. Younger age, lack of social support, expectations of interpersonal benefit, lower appraisals of manageability, and an avoidant coping style were related to more psychological symptoms at all time points. The latter three were mediated by stress. No religious affiliation, unemployment, history of psychological problems, less social support, expectations of negative health consequences, and less positive appraisals were related to lower well-being at all time points., Conclusions: This study identified indicators of a lower mental health status among living kidney donors. Professionals should examine this profile before donation and the need for extra psychological support in relation to the number and magnitude of the identified indicators. Interventions should be focused on the changeable factors (e.g., expectations), decreasing stress/psychological symptoms, and/or increasing well-being. Statement of contribution What is already known on this subject? Until now, research on psychological outcomes after living kidney donation revealed that mental health remained the same for the majority of living kidney donors, while mental health improved or deteriorated for a minority after donation. In reaction to these findings, many psychosocial screening guidelines have been developed for potential donors; however, the components of these guidelines are based on professional opinions and experience rather than on longitudinal empirical data. There is a lack of research that identifies pre-donation donor characteristics that are related to a lower mental health among donors. Such studies are essential in order to tailor psychosocial support during the donation process. What does this study add? Components that are mostly included in psychosocial screening guidelines for potential living kidney donors are not predictive of deterioration, nor increase, in mental health after donation, except for the lack of a partner. Therefore, there is little evidence on the necessity of rejecting potential donors based on these psychological criteria. The following psychological risk factors are predictive of the absolute level of donors' mental health during the donation process: A history of psychological problems, expectations of interpersonal benefit and negative health outcomes, an avoidant coping style, lack of social support, appraisals of the donation process as an unmanageable and/or negative event, a younger age, no religious affiliation, and unemployment. We argue that potential donors should not be rejected for donation based on these factors, but the indicators should be used to identify donors who might be in need for more psychological support., (© 2016 The British Psychological Society.)

Objective: The risk of hepatocellular carcinoma (HCC) is increased in patients with metabolic syndrome (MS), possibly related to nonalcoholic fatty liver disease (NAFLD). As histological features of NAFLD may regress in cirrhosis, we compared steatosis versus steatohepatitis in the nontumoral liver of noncirrhotic HCC patients., Patients and Methods: A retrospective clinicopathological analysis was carried out in 91 noncirrhotic HCC patients. Patients were divided into three subgroups: that is, patients with: (1) MS without other risk factors for underlying liver disease, (2) no underlying risk factors, or (3) other risk factors (with or without MS). The NAFLD activity score (NAS) less than 3 was classified as no steatohepatitis, NAS 3-4 as borderline steatohepatitis, and NAS 5 or more as definite steatohepatitis., Results: Eleven (12%) patients had MS without other risk factors (group 1). In the nontumoral liver, significant steatosis (≥5% of hepatocytes) was generally present (in 10/11 patients), with mild lobular inflammation and absence of ballooning in most cases. Absence of steatohepatitis, borderline steatohepatitis, and definite steatohepatitis were found in 55, 45, and 0% of cases, respectively. In groups 2 and 3, significant steatosis was frequently present (in 16/37 and 21/43 patients, respectively). Absence of steatohepatitis, borderline steatohepatitis, and definite steatohepatitis were found in 84, 16, and 0% of cases (group 2), respectively, in 77, 23, and 0% of cases (group 3)., Conclusion: In noncirrhotic HCC patients, histological steatosis was frequently present, whereas overt steatohepatitis did not occur. These findings may be relevant for HCC pathogenesis in NAFLD.

Goals and Background: Spontaneous rupture is a rare complication of hepatocellular carcinoma (HCC). Treatment options consist of transcatheter arterial embolization (TAE), hepatic resection, and conservative therapy. The best approach is under debate., Study: This study presents a review of clinical data of patients with a ruptured HCC admitted to a European tertiary care center., Results: Eleven patients were included; six (55%) had underlying cirrhosis. The majority of patients (73%) had no previous history of HCC. Spontaneous HCC rupture was diagnosed using abdominal computed tomography with or without a diagnostic paracentesis. Computed tomography showed one or two tumors in eight (73%) patients; the other patients had multiple tumors or diffuse infiltrative HCC. Seven (64%) patients were initially treated by TAE and one (9%) patient underwent hepatic resection. The remaining three (27%) patients, all of whom had liver cirrhosis, received conservative therapy. Two patients initially treated by TAE underwent a delayed resection and ultimately received systemic therapy. Overall, at the end of the follow-up period, three patients were still alive at 84, 991, and 1026 days after the initial presentation. Eight (73%) patients had died after a median of 88 days (range 7-417). One year after presentation, none of the conservatively treated patients was alive compared with three out of seven (43%) patients treated with TAE with or without delayed resection., Conclusion: Patients with a spontaneously ruptured HCC have a poor prognosis. In selected patients, however, prolonged survival is possible using TAE as initial therapy with or without a delayed resection and systemic therapy.

Introduction: Living kidney donors comprise a unique group of "patients", undergoing an operation for the benefit of others. The informed consent process is therefore valued differently. Although this is a team effort, the surgeon is responsible for performing the donor nephrectomy, and often the one held accountable, should adverse events occur. Although there is some consensus on how the informed consent procedure should be arranged, practices vary. The aim of this study was to evaluate the surgical informed consent procedure for live donor nephrectomy, with special regards to disclosure of complications., Methods: A web-based survey was sent to all kidney transplant surgeons (n = 50) in eight transplant centers with questions regarding the local procedure and disclosure of specific details., Results: Response rate was 98% (n = 49), of which 32 (65%) were involved in living donor education; overall, transplant- (50%), vascular- (31%), and abdominal surgeons (13%), and urologists (6%) performed donor nephrectomies in the eight centers. Informed consent procedures varied, ranging from assumed to signed consent. Bleeding was the only complication every surgeon mentioned. Risk of death was always mentioned by 16 surgeons (50%), sometimes by 13 (41%), three surgeons (9%) never disclosed this disastrous complication. Reported mortality rates ranged from 0.003% to 0.1%. Mentioning frequencies for all other complications varied., Conclusion: Important complications are not always disclosed during the surgical informed consent process for live donor nephrectomy. Informed consent procedures vary. To optimally prepare living kidney donors for the procedure, a standardized informed consent procedure for live donor nephrectomy is highly recommended., (Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)-assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta-analysis on the impact of CT-assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11-3.05, p = 0.02) and 1.72 (95% confidence interval 0.99-3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End-stage Liver Disease score. Less-consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)