Good outcomes after repeated pediatric liver retransplantations: A justified procedure even in times of organ shortage.

BACKGROUND: Pediatric liver transplantations generally represent advanced surgery for selected patients. In case of acute or chronic graft failure, biliary or vessel complications, a retransplantation (reLT) can be necessary. In these situations massive adhesions, critical patient condition or lack of good vessels for anastomosis often are problematic. METHODS: Between 2008 and 2021, 208 pediatric patients received a liver transplantation at our center. Retrospectively, all cases with at least one retransplantation were identified and stored in a database. Indication, intra- and postoperative course and overall survival (OS) were analyzed. RESULTS: Altogether 31 patients (14.9%) received a reLT. In 22 cases only one reLT was done, 8 patients received 2 reLTs and 1 patient needed a fourth graft. Median age for primary transplantation, first, second and third reLT was 14 (range: 1-192 months), 60.5 (range: 1-215 months), 58.5 (range: 14-131 months) and 67 months, respectively. Although biliary atresia (42%) and acute liver failure (23%) represented the main indications for the primary liver transplantation, acute and chronic graft failure (1st reLT: 36%, 2nd reLT: 38%), hepatic artery thrombosis (1st reLT: 29%, 2nd reLT: 25%, 3rd reLT: 100%) and biliary complications (1st reLT: 26%, 2nd reLT: 37%) were the most frequent indications for reLT. OS was 81.8% for patients with 1 reLT, 87.5% with 2 reLTs and 100% with 3 reLTs. CONCLUSION: Pediatric liver retransplantation is possible with a good outcome even after multiple retransplantations in specialized centers. Nevertheless, careful patient and graft selection, as well as good preoperative conditioning, are essential.

Intraoperative contrast-enhanced ultrasound has an outcome-relevant impact on surgery of primary and metastatic liver lesions.

PURPOSE: Complete resection of the affected tissue remains the best curative treatment option for liver-derived tumors and colorectal liver metastases. In addition to preoperative cross-sectional imaging, contrast-enhanced intraoperative ultrasound (CE-IOUS) plays a crucial role in the detection and localization of all liver lesions. However, its exact role is unclear. This study was designed to evaluate the clinical and oncological impact of using CE-IOUS in the surgical treatment of these diseases. MATERIALS AND METHODS: Over the three-year study period, 206 patients with primary liver tumors and hepatic metastases were enrolled in this prospective, monocentric study to evaluate the impact of CE-IOUS in liver surgery. Secondary outcomes included comparing the sensitivity and specificity of CE-IOUS with existing preoperative imaging modalities and identifying preoperative parameters that could predict a strategic impact of CE-IOUS. In addition, the oncological significance of CE-IOUS was evaluated using a case-cohort design with a minimum follow-up of 18 months. RESULTS: CE-IOUS findings led to a change in surgical strategy in 34% of cases (n=70/206). The accuracy in cases with a major change could be confirmed histopathologically in 71.4% of cases (n=25/35). The impact could not be predicted using parameters assumed to be clinically relevant. An oncological benefit of a CE-IOUS adapted surgical approach was demonstrated in patients suffering from HCC and colorectal liver metastases. CONCLUSION: CE-IOUS may significantly increase R0 resection rates and should therefore be used routinely as an additional staging method, especially in complex liver surgery.

Survival Difference of Endometrial Cancer Patients with Peritoneal Metastasis Receiving Cytoreductive Surgery (CRS) with and without Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Systematic Review and Meta-Analysis.

Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected additional survival benefits of CRS plus HIPEC over CRS only. Twenty-one and ten studies with a total number of 1116 and 152 cases investigating CRS only and CRS plus HIPEC were identified, respectively. When all articles were analyzed, the 1-year survival rate was 17.60% higher for CRS plus HIPEC (82.28% vs. 64.68%; p = 0.0102). The same tendency was observed for the 2-year (56.07% vs. 36.95%; difference: 19.12%; p = 0.0014), but not for the 5-year (21.88% vs. 16.45%; difference: 5.43%; p = 0.3918) survival rates. The same clinical significance, but statistically less strong observations, could be made if only the studies published after 2010 were investigated (1-year survival rate: 12.08% and p = 0.0648; 2-year survival rate: 10.90% and p = 0.0988). CRS remains one of the core elements of ECPM treatment, but the addition of HIPEC to CRS can increase the positive clinical outcome, especially in the first 2 years.

Immune profile of patients with peritoneal carcinomatosis selected for CRS-HIPEC therapy.

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal carcinomatosis (PC) from colorectal cancer (CRC), which is otherwise a terminal stage of disease. Nevertheless, survival outcomes are only marginally superior to other treatments. This fact highlights the need for better strategies to control intra-abdominal disease recurrence after CRS-HIPEC, including the complementary use of immunotherapies. The aim of this study was therefore to investigate the immune phenotype of T cells in patients with PC. Fifty three patients with CRC (34 patients with PC and 19 patients without PC) were enrolled in a prospective study (clinicaltrials.gov: NCT04108936). Peripheral blood and omental fat were collected to isolate peripheral blood mononuclear cells (PBMCs) and adipose tissue mononuclear cells (ATMCs). These cells were analysed by flow cytometry using a panel focused upon T cell memory differentiation and exhaustion markers. We found a more naïve profile for CD8+ T cells in peripheral blood and intra-abdominal fat of PC patients compared to comparator group (CG) patients. Furthermore, there was an over-representation of CD4+ T cells expressing inhibitory receptors in adipose tissue of PC patients, but not in blood. Our description of intraperitoneal T cell subsets gives us a better understanding of how peritoneal carcinomatosis shapes local immune responses.

Early γGT and bilirubin levels as biomarkers for regeneration and outcomes in damaged bile ducts after liver transplantation.

BACKGROUND: Early patient and allograft survival after liver transplantation (LT) depend primarily on parenchymal function, but long-term allograft success relies often on biliary-tree function. We examined parameters related to cholangiocyte damage that predict poor long-term LT outcomes after donation after brain death (DBD). METHODS: Sixty bile ducts (BD) were assessed by a BD damage-score and divided into groups with "major" BD-damage (n = 33) and "no relevant" damage (n = 27) during static cold storage. Patients with "major" BD damage were further investigated by measuring biliary excretion parameters in the first 14 days post-LT (followed-up for 60-months). RESULTS: Patients who received LT showing "major" BD damage had significantly worse long-term patient survival, versus grafts with "no relevant" damage (p = .03). When "major" BD damage developed, low bilirubin levels (p = .012) and high gamma-glutamyl transferase (GGT)/bilirubin ratio (p = .0003) were evident in the early post-LT phase (7-14 days) in patients who survived (> 60 months), compared to those who did not. "High risk" patients with bile duct damage and low GGT/bilirubin ratio had significantly shorter overall survival (p < .0001). CONCLUSIONS: Once "major" BD damage occurs, a high GGT/bilirubin ratio in the early post-operative phase is likely indicator of liver and cholangiocyte regeneration, and thus a harbinger of good overall outcomes. "Major" BD damage without markers of regeneration identifies LT patients that could benefit from future repair therapies.

Biological abdominal wall expansion in pediatric liver recipients after transplantation with large-for-size organs.

BACKGROUND: After pediatric split liver transplantation, intra-abdominal loss of domain due to large-for-size left lateral grafts is a frequent problem for fascial closure and potentially leads to reduced liver perfusion and abdominal compartment syndrome. Therefore, delayed fascial closure with the use of temporary silastic meshes and reoperation or alternative fascial bridging procedures are necessary. METHODS: Between March 2019 and October 2021, biologic meshes were used for abdominal wall expansion in 6 cases of pediatric split liver transplantation. These cases were analyzed retrospectively. RESULTS: One male and 5 female children with median age of 6 months (range: 0-57 months) and weight of 6 kg (range: 3.5-22 kg) received a large-for-size left lateral graft. Graft-to-recipient weight ratio (GRWR) was 4.8% (range: 1.5%-8.5%) in median. Biologic mesh implantation for abdominal wall expansion was done in median 7 days (range: 3-11 days) after transplantation when signs of abdominal compartment syndrome with portal vein thrombosis in 3 and of the liver artery in 1 case occurred. In 2 cases, bovine acellular collagen matrix and 4 cases ovine reinforced tissue matrix was used. Median follow-up was 12.5 months (range: 4-28 months) and showed good liver perfusion by sonography and normal corporal development without signs of ventral hernia. One patient died because of fulminant graft rejection and emergency re-transplantation 11 months after the initial transplantation. CONCLUSIONS: Biologic meshes can be used as safe method for abdominal wall expansion to achieve fascial closure in large-for-size liver transplant recipients. Usage for primary fascial closure can be considered in selected patients.

[Contrast-Enhanced Ultrasound of Fibrolamellar Hepatocellular Carcinoma]. / Kontrastmittelsonografie eines fibrolamellären hepatozellulären Karzinoms.

We present the case of a 24-year-old male patient, who was admitted for endoscopy due to sustained pain in the upper abdomen with nausea and postprandial fullness without vomiting for more than 5 months. In the physical examination, an epigastric induration was found. Endoscopy revealed an external impression of the proximal duodenum. Beyond that, normal findings could be ascertained in gastroscopy and ileo-colonoscopy. Abdominal ultrasound identified a large hypoechoic lesion in the left liver lobe with a sharp delineation. Along the upper mesenteric vessels, enlarged lymphnodes were visible with contact to the proximal duodenum. Contrast-enhanced ultrasound (CE-US) was conducted and revealed the typical perfusion pattern of hepatocellular carcinoma. For further assessment, an ultrasound-guided core-biopsy of the lesion was performed. The histopathological evaluations resulted in the diagnosis of a hepatocellular carcinoma of fibrolamellar subtype.With the present case, we want to illustrate the perfusion pattern of a fibrolamellar hepatocellular carcinoma in contrast-enhanced ultrasound. Even though the tumor tissue is surrounded by lamellar bands of fibrosis with collagen-rich fibers, the perfusion pattern is consistent with the previously known appearance of HCC in CE-US.

Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Predictors of portal vein complications after pediatric liver transplantation: A German center experience.

BACKGROUND: Portal vein complications (PVCs) after pediatric liver transplantation (LT) are sometimes asymptomatic, especially in the early phase, and can threaten both the graft and patient's survival. Therefore, the purpose of this study is to analyze the risk factors for portal vein thrombosis (PVT) and portal vein stenosis (PVS) after pediatric LT. METHODS: All pediatric patients (n = 115) who underwent primary LT at Regensburg University Hospital between January 2010 and April 2017 were included in this study. The pre-, intra-, and postoperative parameters of all patients were retrospectively reviewed and risk factors for both PVT and PVS were analyzed. RESULTS: Of the 115 patients, living donor LT was performed on 57 (49.5%) patients, and biliary atresia was the primary diagnosis in 65 patients (56%). After pediatric LT, 9% of patients developed PVT, and 16.5% developed PVS. Patient weight ≤7 kg [odds ratio (OR) 9.35, 95% confidence interval (CI) 1.03-84.9, p = .04] and GRWR >3% (OR 15.4, 95% CI 1.98-129.5, p = .01) were the independent risk factors for the development of PVT and PVS, respectively upon multivariate analysis. The overall patient survival rates at 1, 3, and 5 years were 91%, 90%, and 89%, respectively, and there was no difference in patient survival among those with and without PVCs. CONCLUSIONS: Pediatric patients with body weight <7 kg and/or receiving a graft with GRWR >3% may develop PVCs and so require certain surgical modifications, close follow-up, and prophylactic anticoagulant therapy following transplant.

Resection of oesophageal and oesophagogastric junction cancer liver metastases - a summary of current evidence.

PURPOSE: Metastatic oesophageal cancer is commonly considered as a palliative situation with a poor prognosis. However, there is increasing evidence that well-selected patients with a limited number of liver metastases (ECLM) may benefit from a multimodal approach including surgery. METHODS: A systematic review of the current literature for randomized trials, retrospective studies, and case series with patients undergoing hepatectomies for oesophageal and oesophagogastric junction cancer liver metastases was conducted up to the 31st of August 2021 using the MEDLINE (PubMed) and Cochrane Library databases. RESULTS: A total of 661 articles were identified. After removal of duplicates, 483 articles were screened, of which 11 met the inclusion criteria. The available literature suggests that ECLM resection in patients with liver oligometastatic disease may lead to improved survival and even long-term survival in some cases. The response to concomitant chemotherapy and liver resection seems to be of significance. Furthermore, a long disease-free interval in metachronous disease, low number of liver metastases, young age, and good overall performance status have been described as potential predictive markers of outcome for the resection of liver metastases. CONCLUSION: Surgery may be offered to carefully selected patients to potentially improve survival rates compared to palliative treatment approaches. Studies with standardized patient selection criteria and treatment protocols are required to further define the role for surgery in ECLM. In this context, particular consideration should be given to neoadjuvant treatment concepts including immunotherapies in stage IVB oesophageal and oesophagogastric junction cancer.

[Bowel resections for Crohn's disease: developments over the last three decades]. / Drei Dekaden Darmresektionen bei Patienten mit M. Crohn.

BACKGROUND: The present observational study demonstrates developments of surgery in Crohn's disease patients undergoing bowel resection at two tertiary referral centers during the recent 3 decades. METHODS: Consecutive patients undergoing intestinal resections were included. Exclusion criteria were: resection for malignancy, mere stoma formation and closure, bowel resections for other reasons than Crohn's disease, abdomino-perineal resections for anal fistula. Data collection was retrospective between 1992 and 2004, and prospective thereafter. Six time periods were compared: 1992-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015, and 2016-2020. RESULTS: Between 2000 and 2015 several significant developments could be observed: decline in preoperative steroid intake, increase in preoperative intake of immunomodulators and biologic agents; abandonment of preoperative mechanical bowel preparation, increase in surgery for penetrating disease and more patients with previous bowel resections, increase in laparoscopy use, stoma rate and postoperative morbidity. Since 2016, mechanical bowel preparation and oral antibiotics were (re)introduced, there was significantly more laparoscopic surgery (67%), preoperative steroid and immunomodulator intake diminished, whereas preoperative biological therapy increased; patients were older and less were active smokers; stoma formation rate and morbidity rate decreased significantly. CONCLUSION: There were several very strong trends in Crohn's disease surgery during the last 3 decades. However, present results cannot be generalized to broader patient' population.

[The use of immuno-oncologic therapy in hepatocellular carcinoma in the context of liver transplantation. An interdisciplinary benefit/risk assessment]. / Der Einsatz der immunonkologischen Therapie beim hepatozellulären Karzinom im Kontext der Lebertransplantation Eine interdisziplinäre Risiko-Nutzen-Abwägung.

BACKGROUND: Multiple systemic therapy options have been recently approved for the treatment of hepatocellular carcinoma (HCC). In particular, immuno-oncology combination therapies can now achieve impressive response rates and significantly prolonged survival with good tolerability. These immuno-oncology (IO)-based combinations are currently not only evaluated for the therapy of advanced HCC, but increasingly also in earlier stages in terms of peri-interventional therapy concepts and also for down-sizing to local therapies. In the context of liver transplantation (LTx), a particularly critical benefit/risk assessment must be made before the use of immunotherapeutics in the context of multimodal concepts, since the risk of a potentially lethal rejection can be significantly increased by immunotherapy. METHODS: This review is based on a selective literature search performed between December 2020 and April 2021 in the PubMed and Cochrane Library databases. Guidelines, expert opinions, and recommendations from professional societies were given special consideration. RESULTS: Nearly one in five LTx in Germany are performed due to HCCs. In this context, LTx is a curative therapy option not only for the underlying liver disease but also for the malignant tumor. Individual case reports indicate that IO therapy prior to LTx may increase the risk of rejection or liver failure after subsequent liver transplantation. Since 2015, immunotherapeutics have also been widely used for tumor therapy in patients after LTx. In small case series, rejection rates of 36%, associated with rejection-related mortality of 20% of treated patients, have been described. A similar incidence of rejection has also been described following the use of immunotherapeutics in patients after other organ transplantations. CONCLUSION: In the context of organ transplantation, IO therapy carries the risk of graft rejection, which can lead to graft loss and also patient death. However, from today's point of view, IO-based therapy can be considered in the context of organ transplantation with a careful benefit/risk assessment.

Diaphragmatic Injuries among Severely Injured Patients (ISS ≥ 16)-An Indicator of Injury Pattern and Severity of Abdominal Trauma.

Background and Objectives: Abdominal trauma among severely injured patients with an injury severity score (ISS) of 16 and above can lead to potentially life-threatening injuries that might need immediate surgical intervention. Traumatic injuries to the diaphragm (TID) are a challenging condition often accompanied by other injuries in the thoracoabdominal region. Materials and Methods: We retrospectively analyzed the occurrence and clinical course of TID among severely injured patients treated at our center between 2008 and 2019 and compared them to other groups of severely injured patients without TID. Results: Thirty-five patients with TID and a median ISS of 41 were treated in the period mentioned above. They were predominantly middle-aged men and mostly victims of blunt trauma as a consequence of motor vehicle accidents. A total of 70.6% had left-sided TID, and in 69.6%, the size of defect was larger than 10 cm. The diagnosis was made with computed tomography (CT) in 68.6% of the cases, while in 25.8%, it was made intraoperatively or delayed by a false-negative initial CT scan, and in 5.7%, an intraoperative diagnosis was made without preoperative CT imaging. Surgical repair was mostly conducted via laparotomy, performing a direct closure with continuous suture. A comparison to 191 patients that required laparotomy for abdominal injuries other than TID revealed significantly higher rates of concomitant injuries to several abdominal organs among patients suffering from TID. Compared to all other severely injured patients treated in the same period (n = 1377), patients suffering from TID had a significantly higher median ISS and a longer mean duration of hospital stay. Conclusions: Our findings show that TID can be seen as an indicator of particularly severe thoracoabdominal trauma that requires increased attention from the treatment team so as not to miss relevant concomitant injuries that require immediate intervention.

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.

BACKGROUND: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. METHODS: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. FINDINGS: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. INTERPRETATION: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. FUNDING: The 7th EU Framework Programme.

Cross-presentation of dead-cell-associated antigens by DNGR-1+ dendritic cells contributes to chronic allograft rejection in mice.

The purpose of this study was to elucidate whether DC NK lectin group receptor-1 (DNGR-1)-dependent cross-presentation of dead-cell-associated antigens occurs after transplantation and contributes to CD8+ T cell responses, chronic allograft rejection (CAR), and fibrosis. BALB/c or C57BL/6 hearts were heterotopically transplanted into WT, Clec9a-/- , or Batf3-/- recipient C57BL/6 mice. Allografts were analyzed for cell infiltration, CD8+ T cell activation, fibrogenesis, and CAR using immunohistochemistry, Western blot, qRT2 -PCR, and flow cytometry. Allografts displayed infiltration by recipient DNGR-1+ DCs, signs of CAR, and fibrosis. Allografts in Clec9a-/- recipients showed reduced CAR (p < 0.0001), fibrosis (P = 0.0137), CD8+ cell infiltration (P < 0.0001), and effector cytokine levels compared to WT recipients. Batf3-deficiency greatly reduced DNGR-1+ DC-infiltration, CAR (P < 0.0001), and fibrosis (P = 0.0382). CD8 cells infiltrating allografts of cytochrome C treated recipients, showed reduced production of CD8 effector cytokines (P < 0.05). Further, alloreactive CD8+ T cell response in indirect pathway IFN-γ ELISPOT was reduced in Clec9a-/- recipient mice (P = 0.0283). Blockade of DNGR-1 by antibody, similar to genetic elimination of the receptor, reduced CAR (P = 0.0003), fibrosis (P = 0.0273), infiltration of CD8+ cells (p = 0.0006), and effector cytokine levels. DNGR-1-dependent alloantigen cross-presentation by DNGR-1+ DCs induces alloreactive CD8+ cells that induce CAR and fibrosis. Antibody against DNGR-1 can block this process and prevent CAR and fibrosis.

Differential effects of heat-inactivated, secretome-deficient MSC and metabolically active MSC in sepsis and allogenic heart transplantation.

Mesenchymal stem cells (MSCs) are used in various clinical and preclinical models for immunomodulation. However, it remains unclear how the immunomodulatory effect of MSC is communicated. MSC-induced immunomodulation is known to be mediated through both MSC-secreted cytokines and direct cell-cell interactions. Recently, it has been demonstrated that metabolically inactive, heat-inactivated MSCs (HI-MSCs) have similar anti-inflammatory capacities in LPS-induced sepsis compared with viable MSC. To further investigate the immunomodulatory effects of MSC, we introduced MSC and HI-MSC in two animal models with different immunological causes. In the first model, allogeneic hearts were transplanted from C57BL/6 mice to BALB/c recipients. MSC in combination with mycophenolate mofetil (MMF) significantly improved graft survival compared with MMF alone, whereas the application of HI-MSC had no effect on graft survival. We revealed that control MSC dose-dependently inhibited CD3+ and CD8+ T-cell proliferation in vitro, whereas HI-MSC had no effect. In the second model, sepsis was induced in mice via cecal ligation and puncture. HI-MSC treatment significantly improved the overall survival, whereas control MSCs had no effect. in vitro studies demonstrated that HI-MSCs are more effectively phagocytosed by monocytes than control MSCs and induced cell death in particular of activated CD16+ monocytes, which may explain the immune protective effect of HI-MSC in the sepsis model. The results of our study demonstrate that MSC-mediated immunomodulation in sepsis is dependent on a passive recognition of MSC by monocytes, whereas fully functional MSCs are required for inhibition of T-cell-mediated allograft rejection.

Influence of early biliary complications on survival rates after pediatric liver transplantation-A positive outlook.

BACKGROUND: Early biliary complications (EBC) constitute a burden after pediatric liver transplantation frequently requiring immediate therapy. We aimed to assess the impact of EBC on short- and long-term patient and graft survival as well as post-transplant morbidity. METHODS: We analyzed 121 pediatric liver transplantations performed between 1984 and 2019 at the Medical University of Innsbruck for the occurrence of early (<90 days) biliary complications and investigated the influence of EBC on patient and graft survival. RESULTS: Early biliary complications occurred in 30 (24.8%) out of the 121 pediatric liver transplant recipients. Patient survival at 15 years (89.2% vs. 84.2%, p = .65) and all-cause (82.5% vs. 74.0%) and death-censored graft survival (82.5% vs. 75.1%, p = .71) at 10 years were similar between the EBC and the non-EBC group. The EBC group had a significantly longer ICU (25 vs. 16 days, p < .001) and initial hospital stay (64 vs. 42 days, p = .002). Livers of patients with EBC were characterized by multiple bile ducts (33.3% vs. 13.2%, p = .027), and patients with EBC had a higher risk to develop late biliary complications (OR 2.821 [95% CI 1.049-7.587], p = .044) and bowel obstruction/perforation (OR 4.388 [95% CI 1.503-12.812], p = .007). CONCLUSION: Early biliary complications after pediatric liver transplantation is frequent. The occurrence of EBC significantly increased post-transplant morbidity without affecting mortality. Multiple bile ducts were the only risk factor for the development of EBC in our cohort.

Intraoperative Characterization of Pancreatic Tumors Using Contrast-Enhanced Ultrasound and Shear Wave Elastography for Optimization of Surgical Strategies.

OBJECTIVES: To evaluate intraoperative contrast-enhanced ultrasound (IoCEUS) and intraoperative shear wave elastography (IoSWE) for characterization of focal pancreatic lesions (FPLs) in correlation with postoperative histologic results. Thereby, the impact of intraoperative ultrasound (US) on pancreas surgery was evaluated. METHODS: Intraoperative CEUS and SWE data from 54 patients, who underwent pancreas surgery between 2017 and 2019, were analyzed retrospectively. Ultrasound examinations were performed with multifrequency linear/T-shaped transducers (3-9 MHz) on a high-end US device (LOGIQ E9; GE Healthcare, Chicago, IL). To analyze FPL stiffness by SWE, regions of interest were placed to measure the shear wave speed (meters per second) and stiffness (kilopascals). After intravenous bolus injections of 2.4 to 10 mL of sulfur hexafluoride microbubbles, a dynamic analysis of FPL microvascularization from arterial to late phases was performed using IoCEUS considering hypoenhancement/irregular vascularization of macrocystic/small solid FPL malignancy criteria. Ultrasound findings were correlated with postoperative histologic results. The impact of intraoperative US on surgery was documented in each case. RESULTS: Of 54 FPLs, IoCEUS could correctly characterize 39 of 39 malignant and 6 of 15 benign FPLs; IoSWE 29 of 39 as malignant and 7 of 15 as benign. Intraoperative CEUS's sensitivity was 100%; specificity, 40%; accuracy, 83.3%; positive predictive value, 81.3%; and negative predictive value, 100% (P < .05). Applying cutoff values of 3 m/s and 28.7 kPa, SWE's sensitivity was 74.4%; specificity, 46.7%; accuracy, 66.7%; positive predictive value; 78.4%; and negative predictive value, 41.2% for cancer detection (P < .05). The combined use of both techniques showed an accuracy rate of 76%, sensitivity of 74.4%, and specificity of 33.3%. In 29.6%, US results had an immediate impact on surgery. CONCLUSIONS: Intraoperative SWE and CEUS are highly valuable techniques for intraoperative characterization of FPLs. Although IoCEUS proved to be superior to IoSWE, the combined use can be helpful in particular cases.

[Prevention of gastrointestinal cancer]. / Prävention gastrointestinaler Tumore.

Throughout the past decades, considerable progress has been made in the (early) diagnosis and treatment of gastrointestinal cancers. However, the prognosis for advanced stages of gastrointestinal tumors remains limited for many patients and approximately one third of all tumor patients die as a result of gastrointestinal tumors. The prevention and early detection of gastrointestinal tumors is therefore of great importance.For this reason, we summarize the current state of knowledge and recommendations for the primary, secondary and tertiary prevention of esophageal, stomach, pancreas, liver and colorectal cancer in the following.