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For a highly selected group of patients with unresectable perihilar cholangiocarcinoma (pCCA), liver transplantation (LT) is a treatment option. The Dutch screening protocol comprises nonregional lymph node (LN) assessment by EUS, and whenever LN metastases are identified, further LT screening is precluded. The aim of this study is to investigate the yield of EUS in patients with pCCA who are potentially eligible for LT. In this retrospective, nationwide cohort study, all consecutive patients with suspected unresectable pCCA who underwent EUS in the screening protocol for LT were included from 2011 to 2021. During EUS, sampling of a "suspicious" nonregional LN was performed based on the endoscopist's discretion. The primary outcome was the added value of EUS, defined as the number of patients who were precluded from further screening because of malignant LNs. A total of 75 patients were included in whom 84 EUS procedures were performed, with EUS-guided tissue acquisition confirming malignancy in LNs in 3 of 75 (4%) patients. In the 43 who underwent surgical staging according to the protocol, nonregional LNs with malignancy were identified in 6 (14%) patients. Positive regional LNs were found in 7 patients in post-LT-resected specimens. Our current EUS screening for the detection of malignant LNs in patients with pCCA eligible for LT shows a limited but clinically important yield. EUS with systematic screening of all LN stations, both regional and nonregional, and the sampling of suspicious lymph nodes according to defined and set criteria could potentially increase this yield. [Display omitted] [ABSTRACT FROM AUTHOR]

Evaluation of morbidity and mortality after hepatic resection often lacks stratification by extent of resection or diagnosis. Although a liver resection for different indications may have technical similarities, postoperative outcomes differ. The aim of this systematic review and meta-analysis was to determine the risk of major complications and mortality after resection of intrahepatic cholangiocarcinoma. Meta-analysis was performed to assess postoperative mortality (in-hospital, 30-, and 90-day) and major complications (Clavien-Dindo grade ≥III). A total of 32 studies that reported on 19,503 patients were included. Pooled in-hospital, 30-day, and 90-day mortality were 5.9% (95% confidence interval 4.1–8.4); 4.6% (95% confidence interval 4.0–5.2); and 6.1% (95% confidence interval 5.0–7.3), respectively. Pooled proportion of major complications was 22.2% (95% confidence interval 17.7–27.5) for all resections. The pooled 90-day mortality was 3.1% (95% confidence interval 1.8–5.2) for a minor resection, 7.4% (95% confidence interval 5.9–9.3) for all major resections, and 11.4% (95% confidence interval 6.9–18.7) for extended resections (P =.001). Major complications were 38.8% (95% confidence interval 29.5–49) after a major hepatectomy compared to 11.3% (95% confidence interval 5.0–24.0) after a minor hepatectomy (P =.001). Asian studies had a pooled 90-day mortality of 4.4% (95% confidence interval 3.3–5.9) compared to 6.8% (95% confidence interval 5.6–8.2) for Western studies (P =.02). Cohorts with patients included before 2000 had a pooled 90-day mortality of 5.9% (95% confidence interval 4.8–7.3) compared to 6.8% (95% confidence interval 5.1–9.1) after 2000 (P =.44). When informing patients or comparing outcomes across hospitals, postoperative mortality rates after liver resection should be reported for 90-days with consideration of the diagnosis and the extent of liver resection. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the incidence and risk factors of primary and secondary liver failure after major liver resection for perihilar cholangiocarcinoma. All patients who underwent a major liver resection for presumed perihilar cholangiocarcinoma between 2000 and 2020 at 2 tertiary-referral hospitals were included. Liver failure was defined according to the International Study Group for Liver Surgery criteria, and only grade B/C was considered clinically relevant. Primary liver failure was defined as failure without any underlying postoperative cause, and secondary liver failure was defined as liver failure with an onset after an underlying postoperative complication as a cause. The incidence of liver failure and 90-day mortality were 20.9% and 17.0% in the 253 included patients, respectively. The incidences of primary liver failure was 9.1% and secondary liver failure was 11.9%. Abdominal sepsis, portal vein thrombosis, and arterial thrombosis were the most frequent causes. The absence of preoperative remnant liver assessment and blood loss were independent risk factors for primary liver failure. Independent risk factors for secondary liver failure were Eastern Cooperative Oncology group performance status, percutaneous biliary drainage, and preoperative cholangitis. Liver failure after major liver resection for perihilar cholangiocarcinoma occurred in 1 of every 5 patients. The proposed subdivision into primary and secondary liver failure could help to understand differences in outcomes between centers and help to reduce liver failure. [ABSTRACT FROM AUTHOR]

Background: The aim was to compare the prognostic accuracy of cross-sectional imaging of the 7th and 8th editions of the American Joint Committee on Cancer(AJCC) staging system for perihilar cholangiocarcinoma(PHC). Methods: All patients with PHC between 2002 and 2014 were included. Imaging at the time of presentation was reassessed and clinical tumor–node–metastasis (cTNM) stage was determined according to the 7th and 8th editions of the AJCC staging system. Comparison of the prognostic accuracy was performed using the concordance index (c-index). Results: A total of 248 PHC patients were included;45 patients(18.1%) underwent a curative-intent resection, whereas 203 patients(81.9%) did not because they were unfit for surgery or were diagnosed with locally advanced or metastatic disease during workup. Prognostic accuracy was comparable between the 7th and 8th editions (c-index 0.57 vs 0.58). For patients who underwent a curative-intent resection, the prognostic accuracy of the 8th edition (0.67) was higher than the 7th (0.65). For patients who did not undergo a curative-intent resection, the prognostic accuracy was poor in both the 7th as the 8th editions (0.54 vs 0.57). Conclusion: The 7th and 8th editions of the AJCC staging system for PHC have comparable prognostic accuracy. Prognostic accuracy was particularly poor in unresectable patients. [ABSTRACT FROM AUTHOR]

Background: This study analyzes the outcome of esophageal resection in patients 70 or more years of age, compared with patients aged less than 70 years and identifies risk factors for worse outcome in the elderly. Methods: Comorbidity, postoperative morbidity, in-hospital mortality and survival rates were compared between 811 patients aged less than 70 years and 250 patients aged 70 years or more who underwent esophagectomy for esophageal cancer in a single high-volume center from 1985 to 2005. Results: Groups were similar regarding surgical approach, resectability, and tumor stage. More patients aged 70 years or more had cardiovascular and respiratory concomitant disease. Among patients aged 70 years or more, the prevalence of adenocarcinoma and Barrett''s transformation was higher (67% versus 53% for patients aged less than 70 years, and 22% versus 15%, respectively). There were no differences in surgical complications (20% versus 17%). Nonsurgical complications occurred more in patients aged 70 years or more (35% versus 27%) and operative mortality was higher among elderly patients (8.4 versus 3.8%), as was in-hospital mortality (11.6% versus 5.4%). The disease-specific 5-year survival was lower for patients aged 70 years or more (27% versus 34%). The 1-year survival, reflecting the impact of operative morbidity and mortality, was 58% for patients aged 70 years or more and 68% for the patients aged less than 70 years (p = 0.002). Among patients aged 70 years or more, respiratory comorbidity and thoracoabdominal resection were risk factors for the occurrence of nonsurgical complications and respiratory comorbidity for in-hospital mortality. Conclusions: Older patients have increased operative and in-hospital mortality and decreased 5-year survival after esophageal resection for cancer. Our results indicate that especially thoracoabdominal resection for esophageal carcinoma should be carefully considered for patients older than 70 years who suffer from respiratory disease. [Copyright &y& Elsevier]

Background: Esophagectomy with gastric tube reconstruction is the surgical treatment for cancer of the esophagus. Perfusion of the anastomotic site of the tube depends exclusively on microcirculation, making it susceptible to hypoperfusion. It is unknown whether vasodilatation is superior to increased perfusion pressure to improve gastric tissue perfusion of the anastomosis. Methods: We performed a gastric tube reconstruction in 12 pigs, mean body weight 32 ± 2 kg. Besides systemic hemodynamic parameters, gastric microvascular blood flow (MBF) was assessed with laser Doppler flowmetry and gastric microvascular HbO2 saturation (μHbSO2) and Hb concentration (μHbcon) with spectrophotometry. Animals were randomized over 2 groups: with and without intravenous nitroglycerin (NTG). In both groups, mean arterial pressure (MAP) was increased from 50 to 110 mmHg with infusion of norepinephrine; in the NTG group, central venous pressure was maintained below 10 mmHg throughout the experiment with NTG. Results: Except for central venous and pulmonary capillary wedge pressures, all hemodynamic parameters were similar in both groups. Especially in corpus and fundus, MBF decreased following surgery. However, overall MBF was significantly higher in the NTG group. Increasing MAP had no effect on fundus MBF. Gastric μHbSO2 and μHbcon were not different between groups and did not change at higher MAP levels. Conclusion: In our experimental model of gastric tube reconstruction, tissue perfusion is severely compromised; this effect is aggravated by systemic hypotension independent from cardiac output. Impaired venous outflow might contribute to this effect and can be counteracted with infusion of nitroglycerine. [Copyright &y& Elsevier]

Since the introduction of the Model for End-stage Liver disease criteria in 2002, more combined liver kidney transplants are performed. Until 2017, no standard allocation policy for combined liver kidney transplant (CLKT) was available and each transplant center decided eligibility for CLKT or liver transplant alone (LTA) on a case-by-case basis. The aim of this systematic review was to compare the clinical outcomes of CLKT compared to LTA in patients with renal dysfunction. Databases were systematically searched for studies published between January 2010 and March 2021. Outcomes were expressed as risk ratios and pooled with a random-effects model. The primary outcome was patient survival. Four studies were included. No differences were observed for mortality risk at 1 year (risk ratio (RR) 1.03 [confidence interval (CI) 0.97–1.09], 3 years (RR 1.06 [CI 0.99–1.13]) and 5 years (RR 1.08 [CI 0.98–1.19]). The risk of graft loss was similar in the first year (RR 1.10 [CI 0.93–1.30], while 3-year risk of graft loss was significantly lower in CLKT patients (RR 1.15 [CI 1.08–1.24]). CLKT has similar short-term graft and patient survival as LTA in patients with renal dysfunction. More data is needed to decide from which KDIGO stage patients benefit the most from CLKT. • This is the first systematic review to compare combined liver-kidney transplants (CLKT) to liver transplant alone (LTA). • Until 2017 no allocation policy existed to determine who was eligible for CLKT or LTA. • CLKT has similar short-term graft and patient survival as LTA in patients with renal dysfunction. • Risk of graft loss was significantly higher at 3 years for LTA compared to CLKT with renal dysfunction. • CLKT seems to be an appropriate therapeutic option for patients with both end stage liver and renal dysfunction. [ABSTRACT FROM AUTHOR]

Background & Aims Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell–mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non–small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. Methods We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Results Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. Conclusions The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. [ABSTRACT FROM AUTHOR]

A global rising organ shortage necessitates the use of extended criteria donors (ECD) for liver transplantation (LT). However, poor preservation and extensive ischemic injury of ECD grafts have been recognized as important factors associated with primary non-function, early allograft dysfunction, and biliary complications after LT. In order to prevent for these ischemia-related complications, machine perfusion (MP) has gained interest as a technique to optimize preservation of grafts and to provide the opportunity to assess graft quality by screening for extensive ischemic injury. For this purpose, however, objective surrogate biomarkers are required which can be easily determined at time of graft preservation and the various techniques of MP. This review provides an overview and evaluation of biomarkers that have been investigated for the assessment of graft quality and viability testing during different types of MP. Moreover, studies regarding conventional graft preservation by static cold storage (SCS) were screened to identify biomarkers that correlated with either allograft dysfunction or biliary complications after LT and which could potentially be applied as predictive markers during MP. The pros and cons of the different biomaterials that are available for biomarker research during graft preservation are discussed, accompanied with suggestions for future research. Though many studies are currently still in the experimental setting or of low evidence level due to small cohort sizes, the biomarkers presented in this review provide a useful handle to monitor recovery of ECD grafts during clinical MP in the near future. [ABSTRACT FROM AUTHOR]

Surgery for perihilar cholangiocarcinoma (pCCA) is associated with high morbidity and mortality rates. The impact of surgery for pCCA may affect patients after discharge. The aim of this study was to investigate all morbidity and mortality during the first year after surgery for pCCA. All consecutive liver resections for suspected pCCA between 2000 and 2019 at two tertiary referral centers were included. All morbidity and mortality until one year after surgery was collected retrospectively, including readmissions and reinterventions. All recurrences within the first year were scored to calculate disease-free survival. In 250 patients, the major morbidity rate was 61% (152/250), in-hospital mortality was 15% (37/250) and 90-day mortality was 16% (40/250). In the 213 discharged patients, 98 patients (46%) suffered 260 surgical complications. These complications required 185 readmissions in 92 patients (43%) and 400 reinterventions in 110 patients (52%), including 330 radiological (83%), 61 endoscopic (15%) and 9 surgical reinterventions (2%). One-year overall survival was 77% and one-year disease-free survival was 70%. Out of the 20 patients who died within the first year after discharge, 15 died of recurrent disease and 3 due to surgery related complications and 2 of unknown causes. Readmissions, reinterventions and complications are frequent throughout the first year after surgery for pCCA in tertiary referral hospitals. These adverse events warrants treatment of these complex patients in high expertise centers offering intensive perioperative care and close follow-up of patients after discharge. [ABSTRACT FROM AUTHOR]

The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset. Furthermore, it sought to identify common prognostic factors across models, and assess methodological quality of the studies in which the models were developed. The PRISMA guidelines were followed. External validation studies of prognostic models for patients with iCCA were searched in 5 databases. Model performance was assessed by discrimination and calibration. Thirteen external validation studies were identified, validating 18 different prognostic models. The Wang model was the sole model with good performance (C-index above 0.70) for overall survival. This model incorporated tumor size and number, lymph node metastasis, direct invasion into surrounding tissue, vascular invasion, Carbohydrate antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Methodological quality was poor in 11/12 statistical models. The Wang model had the highest score with 13 out of 17 points. The Wang model for prognosis after resection of iCCA has good quality and good performance at external validation, while most prognostic models for iCCA have been developed with poor methodological quality and show poor performance at external validation. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Background Although several classifications of perihilar cholangiocarcinoma (PHC) include vascular involvement, its prognostic value has not been investigated. Our aim was to assess the prognostic value of unilateral and main/bilateral involvement of the portal vein (PV) and hepatic artery (HA) on imaging in patients with PHC. Methods All patients with PHC between 2002 and 2014 were included regardless of stage or management. Vascular involvement was defined as apparent tumor contact of at least 180° to the PV or HA on imaging. Kaplan–Meier method with log-rank test was used to compare overall survival (OS) between groups. Cox regression was used for multivariable analysis. Results In total, 674 patients were included with a median OS of 12.2 (95% CI 10.6–13.7) months. Patients with unilateral PV involvement had a median OS of 13.3 (11.0–15.7) months, compared with 14.7 (11.7–17.6) in patients without PV involvement ( p = 0.12). Patients with main/bilateral PV involvement had an inferior median OS of 8.0 (5.4–10.7, p < 0.001) months. Median OS for patients with unilateral HA involvement was 10.6 (9.3–12.0) months compared with 16.9 (13.2–20.5) in patients without HA involvement ( p < 0.001). Patients with main/bilateral HA involvement had an inferior median OS of 6.9 (3.3–10.5, p < 0.001). Independent poor prognostic factors included unilateral and main/bilateral HA involvement, but not PV involvement. Conclusion Both unilateral and main HA involvement are independent poor prognostic factors for OS in patients presenting with PHC, whereas PV involvement is not. [ABSTRACT FROM AUTHOR]

Background Conditional survival is the life expectancy from a point in time for a patient who has survived a specific period after presentation. The aim of the study was to estimate conditional survival for patients with unresectable perihilar cholangiocarcinoma. Methods Patients with unresectable perihilar cholangiocarcinoma from two academic hospitals in the Netherlands between 2002 and 2012 were assessed. A multivariable Cox proportional hazards analysis was performed to identify risk factors associated with overall survival. Survival was estimated using the Kaplan–Meier method to evaluate factors associated with overall survival. Results In total, 572 patients were included. Overall survival was 42% at one year and 6% at three years. The conditional chance of surviving three years was 15% at 1 year and increased to 38% at 2 years. Independent poor prognostic factors for overall survival were age ≥65 years, tumor size >3 cm on imaging, bilirubin levels (>250 μmol/L), CA19-9 level at presentation (>1000 U/ml), and suspected distant metastases on imaging. The conditional survival of patients with and without these prognostic factors was comparable after patients survived the first two or more years. Conclusion The conditional chance of surviving for patients with unresectable perihilar cholangiocarcinoma increases with time. Poor prognostic factors become less relevant once patients have survived two years. [ABSTRACT FROM AUTHOR]

Background & Aims Co-inhibitory receptor-ligand interactions fine-tune immune responses by negatively regulating T cell functions. Our aim is to examine the involvement of co-inhibitory receptor-ligand pair PD-1/PD-L1 in regulating rejection after liver transplantation (LT) in humans. Methods PD-L1/PD-1 expression in liver allograft was determined by immunohistochemistry or flow cytometry, and the effect of blockade was studied using graft-infiltrating T cells ex vivo . Five single nucleotide polymorphisms within PD-1 and PD-L1 genes were genotyped in 528 LT recipients and 410 donors, and associations with both early (⩽6 months) and late (>6 months) acute rejection were analyzed using Cox proportional-hazards regression model. The effect of PD-L1 rs4143815 on PD-L1 expression was analyzed using donor hepatic leukocytes. Results PD-L1 was expressed by hepatocytes, cholangiocytes and along the sinusoids in post-transplant liver allografts, and PD-1 was abundantly expressed on allograft-infiltrating T cells. PD-L1 blockade enhanced allogeneic proliferative responses of graft-infiltrating T cells. In the genetic association analysis, donor PD-L1 rs4143815 (CC/CG vs. GG; HR = 0.230; p = 0.002) and recipient PD-1 rs11568821 (AA/AG vs. GG; HR = 3.739; p = 0.004) were associated with acute rejection late after LT in multivariate analysis. Recipients carrying the PD-1 rs11568821 A allele who were transplanted with liver grafts of PD-L1 rs4143815 GG homozygous donors showed the highest risk for late acute rejection. PD-L1 rs4143815 is associated with differential PD-L1 expression on donor hepatic dendritic cells upon IFN-γ stimulation. Conclusion Our data suggest that interplay between donor PD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans. [ABSTRACT FROM AUTHOR]

Despite the introduction of oral vaccines, rotavirus still kills over 450,000 children under five years of age annually. The absence of specific treatment prompts research aiming at further understanding of pathogenesis and the development of effective antiviral therapy, which in turn requires advanced experimental models. Given the intrinsic limitations of the classical rotavirus models using immortalized cell lines infected with laboratory-adapted strains in two dimensional cultures, our study aimed to model infection and antiviral therapy of both experimental and patient-derived rotavirus strains using three dimensional cultures of primary intestinal organoids. Intestinal epithelial organoids were successfully cultured from mouse or human gut tissues. These organoids recapitulate essential features of the in vivo tissue architecture, and are susceptible to rotavirus. Human organoids are more permissive to rotavirus infection, displaying an over 10,000-fold increase in genomic RNA following 24 h of viral replication. Furthermore, infected organoids are capable of producing infectious rotavirus particles. Treatment of interferon-alpha or ribavirin inhibited viral replication in organoids of both species. Importantly, human organoids efficiently support the infection of patient-derived rotavirus strains and can be potentially harnessed for personalized evaluation of the efficacy of antiviral medications. Therefore, organoids provide a robust model system for studying rotavirus–host interactions and assessing antiviral medications. [ABSTRACT FROM AUTHOR]

Human cholangiocyte organoids are promising for regenerative medicine applications, such as repair of damaged bile ducts. However, organoids are typically cultured in mouse tumor-derived basement membrane extracts (BME), which is poorly defined, highly variable and limits the direct clinical applications of organoids in patients. Extracellular matrix (ECM)-derived hydrogels prepared from decellularized human or porcine livers are attractive alternative culture substrates. Here, the culture and expansion of human cholangiocyte organoids in liver ECM(LECM)-derived hydrogels is described. These hydrogels support proliferation of cholangiocyte organoids and maintain the cholangiocyte-like phenotype. The use of LECM hydrogels does not significantly alter the expression of selected genes or proteins, such as the cholangiocyte marker cytokeratin-7, and no species-specific effect is found between human or porcine LECM hydrogels. Proliferation rates of organoids cultured in LECM hydrogels are lower, but the differentiation capacity of the cholangiocyte organoids towards hepatocyte-like cells is not altered by the presence of tissue-specific ECM components. Moreover, human LECM extracts support the expansion of ICO in a dynamic culture set up without the need for laborious static culture of organoids in hydrogel domes. Liver ECM hydrogels can successfully replace tumor-derived BME and can potentially unlock the full clinical potential of human cholangiocyte organoids. [ABSTRACT FROM AUTHOR]

This overview describes the full spectrum of current pre-clinical and clinical kidney-, liver-, heart- and lung transplantation research performed in Erasmus MC - University Medical Centre in Rotterdam, The Netherlands. An update is provided on the development of a large living donor kidney transplantation program and on optimization of kidney allocation, including the implementation of a domino kidney-donation program. Our current research efforts to optimize immunosuppressive regimens and find novel targets for immunosuppressive therapy, our recent studies on prevention of ischemia-reperfusion-induced graft injury, our newest findings on stimulation of tissue regeneration, our novel approaches to prevent rejection and viral infection, and our latest insights in the regulation of allograft rejection, are summarized. [ABSTRACT FROM AUTHOR]

Background & Aims: Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though the exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive of the development of ITBL after liver transplantation. Methods: Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222, and CDmiR-296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n=20) and grafts without biliary strictures (n=37) were compared. Results: MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (p <0.01) and were identified as an independent risk factor by multivariate analysis (p <0.01, HR: 6.89). The discriminative power of HDmiRs/CDmiRs in perfusates was validated by analysis of separate brain death- (DBD) and cardiac death donors (DBD; p ⩽0.016) and was superior to expression in liver biopsies (C=0.77 in perfusates vs. C<0.50 in biopsies). Conclusions: This study demonstrates that differential release of CDmiRs during graft preservation is predictive of the development of ITBL after liver transplantation. This provides new evidence for the link between graft-related bile duct injury and the risk for later development of ITBL. [Copyright &y& Elsevier]

A correction to the article "MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation," which appeared in a previous issue of the periodical, is presented.