Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

COVID-19 in cancer patients: clinical characteristics and outcome-an analysis of the LEOSS registry.

INTRODUCTION: Since the early SARS-CoV-2 pandemic, cancer patients have been assumed to be at higher risk for severe COVID-19. Here, we present an analysis of cancer patients from the LEOSS (Lean European Open Survey on SARS-CoV-2 Infected Patients) registry to determine whether cancer patients are at higher risk. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 435 cancer patients and 2636 non-cancer patients with confirmed SARS-CoV-2 infection, enrolled between March 16 and August 31, 2020. Data on socio-demographics, comorbidities, cancer-related features and infection course were collected. Age-, sex- and comorbidity-adjusted analysis was performed. Primary endpoint was COVID-19-related mortality. RESULTS: In total, 435 cancer patients were included in our analysis. Commonest age category was 76-85 years (36.5%), and 40.5% were female. Solid tumors were seen in 59% and lymphoma and leukemia in 17.5% and 11% of patients. Of these, 54% had an active malignancy, and 22% had recently received anti-cancer treatments. At detection of SARS-CoV-2, the majority (62.5%) presented with mild symptoms. Progression to severe COVID-19 was seen in 55% and ICU admission in 27.5%. COVID-19-related mortality rate was 22.5%. Male sex, advanced age, and active malignancy were associated with higher death rates. Comparing cancer and non-cancer patients, age distribution and comorbidity differed significantly, as did mortality (14% vs 22.5%, p value < 0.001). After adjustments for other risk factors, mortality was comparable. CONCLUSION: Comparing cancer and non-cancer patients, outcome of COVID-19 was comparable after adjusting for age, sex, and comorbidity. However, our results emphasize that cancer patients as a group are at higher risk due to advanced age and pre-existing conditions.

MRI-guided percutaneous thermoablation as first-line treatment of recurrent hepatic malignancies following hepatic resection: single center long-term experience.

PURPOSE: Hepatic recurrence of liver malignancies is a leading problem in patients after liver resection with curative intention. Thermoablation is a promising treatment approach for patients after hepatic resection, especially in liver-limited conditions. This study aimed to investigate safety, survival, and local tumor control rates of MRI-guided percutaneous thermoablation of recurrent hepatic malignancies following hepatic resection. MATERIAL AND METHODS: Data from patients with primary or secondary hepatic malignancies treated between 2004 and 2018 with MRI-guided percutaneous thermoablation of hepatic recurrence after prior hepatic resection were retrospectively analyzed. Disease-free survival and overall survival rates were calculated using the Kaplan-Meier method. RESULTS: A total of 57 patients with hepatic recurrence (mean tumor size = 18.9 ± 9.1 mm) of colorectal cancer liver metastases (n = 27), hepatocellular carcinoma (n = 17), intrahepatic recurrence of cholangiocellular carcinoma (n = 9), or other primary malignant tumor entities (n = 4) were treated once or several times with MR-guided percutaneous radiofrequency (n = 52) or microwave ablation (n = 5) (range: 1-4 times). Disease progression occurred due to local recurrence at the ablation site in nine patients (15.8%), non-local hepatic recurrence in 33 patients (57.9%), and distant malignancy in 18 patients (31.6%). The median overall survival for the total cohort was 40 months and 49 months for the colorectal cancer group, with a 5-year overall survival rate of 40.7 and 42.5%, respectively. The median disease-free survival was 10 months for both the total cohort and the colorectal cancer group with a 5-year disease-free survival rate of 15.1 and 14.8%, respectively. The mean follow-up time was 39.6 ± 35.7 months. CONCLUSION: MR-guided thermoablation is an effective and safe approach in the treatment of hepatic recurrences in liver-limited conditions and can achieve long-term survival.

[Rosai-Dorfman disease as a rare cause of a pancreatic mass]. / Die Rosai-Dorfman-Erkrankung als seltene Ursache für einen Pankreastumor.

The CT and MRI scans of a 70-year-old male patient revealed a mass in the pancreatic head and a 2.8-cm peripancreatic lymph node. Under steroid therapy the mass did not show regression. Finally, a pancreatoduodenectomy was performed. Histologically, Rosai-Dorfman disease (RDD) was diagnosed. RDD is a rare histiocytic disorder with usually nodal but sometimes also extranodal involvement. Herein we report a rare case of extranodal RDD with intrapancreatic localization.

[Role of the radiologist in surgery of colorectal liver metastases : What should be removed and what must remain]. / Rolle des Radiologen in der Chirurgie kolorektaler Lebermetastasen : Was soll weg und was muss übrig bleiben.

BACKGROUND: The radical resection of colorectal liver metastases is the only curative option for affected patients. If properly performed, surgery provides the chance of long-term tumor-free survival. OBJECTIVE: Summary of the critical interaction points between radiology and surgery in the planning and performance of (complex) liver resections. RESULTS: There are many interaction points between radiology and surgery in the treatment of patients with colorectal liver metastases. Radiology supports surgery by providing detailed information of the localization of metastases, information on liver inflow and outflow as well as basic information on liver quality and function. Perioperatively, it provides interventional treatment options for postoperative complications as well as ablation of non-resectable metastases. CONCLUSION: Complex liver resections can only be performed properly and successfully after thorough planning by an interdisciplinary board of surgeons, radiologists and associated disciplines.

Portal Supply and Venous Drainage of the Caudate Lobe in the Healthy Human Liver: Virtual Three-Dimensional Computed Tomography Volume Study.

OBJECTIVE: The venous vascular anatomy of the caudate lobe is exceptional. The purpose of this study was to assess portal inflow and venous outflow volumes of the caudate lobe. METHODS: Extrahepatic (provided by the first-order branches) versus intrahepatic (provided by the second- to third-order branches) portal inflow, as well as direct (via Spieghel veins) versus indirect (via hepatic veins) venous drainage patterns were analyzed in virtual 3-D liver maps in 140 potential live liver donors. RESULTS: The caudate lobe has a greater intrahepatic than extrahepatic portal inflow volume (mean 55 ± 26 vs. 45 ± 26%: p = 0.0763), and a greater extrahepatic than intrahepatic venous drainage (mean 54-61 vs. 39-46%). Intrahepatic drainage based on mean estimated values showed the following distribution: middle > inferior (accessory) > right > left hepatic vein. CONCLUSIONS: Sacrifice of extrahepatic caudate portal branches can be compensated by the intrahepatic portal supply. The dominant outflow via Spieghel veins and the negligible role of left hepatic vein in caudate venous drainage may suggest reconstruction of caudate outflow via Spieghel veins in instances of extended left hemiliver live donation not inclusive of the middle hepatic vein. The anatomical data and the real implication for living donors must be further verified by clinical studies.

Pancreas-preserving surgical management of grade-C pancreatic fistulas after pancreatic head resection by external wirsungostomy.

PURPOSE: Completion pancreatectomy for grade-C pancreatic fistula is associated with unacceptably high mortality and therefore this strategy should be reassessed. This study presents an update of our experience with a pancreas-preserving technique in the course of salvage re-laparotomy in terms of closure of the open jejunum via segmental resection and external drainage of the pancreas. METHODS: Between April 2004 and January 2015, 292 pancreaticoduodenectomies (PD) with pancreaticojejunostomy (PJ) were performed. Thirteen patients (5 %) underwent salvage re-laparotomy for symptomatic grade-C fistulas, and clinical data were retrospectively analyzed. RESULTS: In all patients, the preservation of the pancreas remnant and external drainage of the pancreatic juice was feasible. Median hospital stay was 58 days (range, 21-142 days). In 4/13 patients (31 %), further reoperations were necessary. In-hospital mortality was 15 % (2/13). 3/13 patients (23 %) were readmitted and two received inpatient non-surgical treatment. To date re-pancreaticojejunostomy was performed in seven of the remaining 11 patients (63 %) after 168 days in median. In 1/7 patients (14 %), a re-operation after re-PJ was necessary. In one patient, externalization of the pancreas juice was chosen as a definite option. In another patient, secretion ceased spontaneously without stasis and normal endocrine function. Neither before nor after re-anastomosis impairment of endocrine function was observed. CONCLUSIONS: Closure of the intestinum and preservation of the pancreas remnant in grade-C pancreatic fistula is easy to perform and can be categorized as a life-saving procedure. Prevention of total pancreatectomy associated with high morbidity and mortality was achieved in all cases.

Liver fluke-infested graft used for living-donor liver transplantation: case report and review of the literature.

Clonorchiasis is a cholangiopathy caused by foodborne trematode parasites, also known as liver flukes. Clonorchiasis is endemic in a wide geographical area extending from Eastern Europe to Southeast Asia. Infested hosts may remain asymptomatic for decades and consequently their liver can become available as a graft. To date, 20 liver transplantations with liver fluke-infested grafts have been reported in the literature. All of them occurred in Asian countries. We, here, report the first case to our knowledge in the Western world of living-donor liver transplantation (LDLT) with an Opisthorchis felineus-infested graft, and present a review of the literature. A 6-month-old girl with decompensated secondary biliary cirrhosis underwent an LDLT with a left lateral graft infested with O. felineus. After prompt diagnosis and adequate therapy, both donor and recipient had an uneventful postoperative course and long-term follow-up. Liver grafts infested with liver flukes do not pose a contraindication to liver donation from deceased or living donors, provided that a correct diagnosis and treatment are performed in a timely fashion.

Roux-en-Y hepatico-jejunostomy for a left segmental graft: Do not twist the loop, stick it!

Biliary complications remain a major challenge for long-term success after LT, as it is, as a rule, the most common technical - early and late - complication that occurs, and because these complications contribute to a significant number of late graft losses and retransplantations. In the pediatric age group, both biliary atresia, as the patient's condition, and the use of a left liver graft, obtained by a liver division technique, make it necessary for the use of a Roux-en-Y jejunal loop for the biliary reconstruction in the majority of cases. A slight modification of the technique is presented, consisting of a straight positioning along the cut surface (rather than the conventional position that results in a harpoon shape). A favorable outcome in terms of a technical complication and graft survival was observed. This way of doing this is an interesting variation and adds to the surgical armamentarium.

Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons Learned from 15 cases at a single centre.

INTRODUCTION: The ALPSS procedure has been recently introduced as an alternative to PVE for liver volume augmentation in cases of planned right trisectionectomy with small future RLV and high risk of PHLF. We retrospectively analysed our single centre experience with 15 ALPPS procedures in order to better assess the limits and indications of the procedure. PATIENTS AND METHODS: The following volumetric parameters were evaluated: total liver volume (TLV), remnant liver volume (RLV), remnant liver volume to total liver volume ratio (RLV/TLV), remnant liver volume to body weight ratio (RLV/BWR) and median volume gain. The ALPPS procedure was usually considered when RLV/TLV < 25 % or RLV/BWR < 0.5. The ALPPS procedure consisted of phase 1 (in situ splitting of the liver), interphase (waiting for liver regeneration) and phase 2 (completion of right trisectionectomy). Postoperative complications were reported according to the Dindo-Clavien classification. Patient survival, late complications and tumour recurrence were analysed. RESULTS: Between November 2010 and September 2013, we performed 15 ALPPS procedures in 10 patients with primary liver tumours (5 h-CCA, 4 i-CCA and 1 HCC) and in 5 with CRLM. The preoperative RLV/TLV ratio was 22.6 % (15.7 - 29.2) and the RLV/BWR 0.46 (0.22 - 0.66). After 10 days (range 8 - 16) the RLV/TLV ratio and RLV/BWR increased up to 36.3 % (30 - 59.2 %) and 0.67 (0.5 - 1.2) respectively, with a median volume gain of 87.2 % (23.8 - 161 %). The time interval between phases 1 and 2 was 13 days (9 - 18). An R0 status was reached in 13 patients and R1 in 2. The overall postoperative morbidity was 66.7 %. After phase 1, 8 patients experienced 19 complications and 7 none. After phase 2, 11 patients experienced 36 complications and 4 none. Four patients died postoperatively after 22 days (9 - 36 days) resulting in a postoperative mortality of 28.7 %. After a median follow-up of 17 months (1 - 33), 10 out of 15 patients are still alive (survival rate 66.6 %). Four patients (2 i-CCA, 1 CRLM, 1 HCC) developed tumour recurrences (2 intrahepatic and 2 extrahepatic). One patient with i-CCA died at POM 4 secondary to peritoneal carcinosis. DISCUSSION: The actual high morbidity and mortality rates related to the ALPPS procedure should lead us to a more cautious selection of the candidates for this operation and restriction of the indications through an accurate work-up based on interdisciplinary cooperation among hepatologists, oncologists, radiologists and surgeons.

Treatment of recurrent genotype 1 hepatitis C post-liver transplantation: single center experience with telaprevir-based triple therapy.

Recurrent HCV infection post-liver transplantation (post-LT) is still a major challenge in the treatment of hepatitis C virus (HCV) infection. In this retrospective analysis we gathered data about treatment response and safety of all 14 post-LT patients who were treated between 2011 and 2013 at our centre with a telaprevir (TVR)-based triple therapy. Seven out of 14 patients completed the full treatment course of 48 weeks. Five patients achieved a SVR 24, while 3 additional HCV RNA-negative patients are still in follow-up (end of treatment, SVR 12 and 22). Four patients discontinued treatment prematurely due to side effects. A virological non-response at TW 4 was seen in 1 patient. Virological breakthrough was observed in 2 patients at TW 16 and 28, respectively; 1 patient displayed a virological relapse after the end of treatment (EOT). Patients with a complicated course post-LT accumulated most of the severe side effects, largely infections. One patient with cholestatic hepatitis died 11 weeks after discontinuation of treatment due to progressive graft failure. In conclusion, TVR-based triple therapy in post-LT patients reveals an acceptable antiviral efficacy. Unfortunately, severe side effects are frequent and often require therapeutic interventions. Therefore, with the approval of less straining DAA like sofosbuvir in sight, TVR-based triple therapy in post-LT patients should be, if possible avoided.

Indications and successes of intestinal transplantation in children in the 21st century: A retrospective cohort study.

AIMS: To report the results and successes of intestinal transplantation (ITx) in the most active European centres, to emphasize that, although it is a difficult procedure, it should remain a therapeutic option for children with total, definitive and complicated intestinal failure when intestinal rehabilitation fails. METHODS: We retrospectively collected data about all patients less than 18 receiving an ITx from 2010 to 2022 in 8 centres, and outcomes in July 2022. RESULTS: ITx was performed in 155 patients, median age 6.9 years, in 45% for short bowel syndromes, 22% congenital enteropathies, 25% motility disorders, and 15% re-transplantations. Indications were multiple in most patients, intestinal failure-associated liver disease in half. The graft was in 70% liver-containing. At last follow up 64% were alive, weaned from parenteral nutrition, for 7.9 years; 27% had died and the graft was removed in 8%, mostly early after ITx. DISCUSSION: ITx, despite its difficulties, can give a future to children with complicated intestinal failure. It should be considered among the therapeutic options offered to patients with a predicted survival rate lower than that after ITx. Patients should be early discussed within multidisciplinary teams in ITx centres, to avoid severe complications impacting the results of ITx, or even to avoid ITx.

Successful ganciclovir treatment of primary cytomegalovirus infection containing the UL97 mutation N510S in an intestinal graft recipient.

In solid organ transplantation, human cytomegalovirus (HCMV) is considered to be the most important viral pathogen. We report a case of a CMV R-/D+ small intestine transplant recipient with a primary CMV infection on valganciclovir prophylaxis. Sequencing of the HCMV DNA for drug resistance-associated mutations revealed the UL97 mutation N510S. This mutation has been initially reported to confer ganciclovir resistance. Based on in vitro recombinant phenotyping, this assumption has recently been questioned. Switching the antiviral treatment to an intravenous regimen of ganciclovir eliminated HCMV DNAemia, showing the in vivo efficacy of ganciclovir for the UL97 mutation N510S. Hence, knowledge of drug efficacy is crucial for an adequate choice of antiviral medication, carefully balancing antiviral potency versus the risk of harmful side effects.

Hepatic 3D cultures but not 2D cultures preserve specific transporter activity for acetaminophen-induced hepatotoxicity.

Primary human hepatocytes (PHH) are the "gold standard" for in vitro toxicity tests. However, 2D PHH cultures have limitations that are due to a time-dependent dedifferentiation process visible by morphological changes closely connected to a decline of albumin production and CYP450 activity. The 3D in vitro culture corresponds to in vivo-like tissue architecture, which preserves functional characteristics of hepatocytes, and therefore can at least partially overcome the restrictions of 2D cultures. Consequently, several drug toxicities observed in vivo cannot be reproduced in 2D in vitro models, for example, the toxic effects of acetaminophen. The objective of this study was to identify molecular differences between 2D and 3D cultivation which explain the observed toxicity response. Our data demonstrated an increase in cell death after treatment with acetaminophen in 3D, but not in 2D cultures. Additionally, an acetaminophen concentration-dependent increase in the CYP2E1 expression level in 3D cultures was detected. However, during the treatment with 10 mM acetaminophen, the expression level of SOD gradually decreased in 3D cultures and was undetectable after 24 h. In line with these findings, we observed higher import/export rates in the membrane transport protein, multidrug resistance-associated protein-1, which is known to be specific for acetaminophen transport. The presented data demonstrate that PHH cultured in 3D preserve certain metabolic functions. Therefore, they have closer resemblance to the in vivo situation than PHH in 2D cultures. In consequence, 3D cultures will allow for a more accurate hepatotoxicity prediction in in vitro models in the future.

A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT.

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.

MRI for evaluation of potential living liver donors: a new approach including contrast-enhanced magnetic resonance cholangiography.

OBJECTIVES: To assess the feasibility of a comprehensive MRI protocol using intrabiliary contrast medium (gadolinium-EOB-DTPA) for evaluation of living liver donors. MATERIAL AND METHODS: In this prospective study, 30 donor candidates for living-related liver transplantation (17 men; 13 women, mean age 37 ± 10.9 years) underwent MRI including MR-angiography (MRA) as well as a conventional T2-weighted MR-cholangiography (MRC) and a contrast-enhanced sequence for depiction of the biliary structures. MRC and MRA images were evaluated for quality on a four-point-scale (score of 0 indicated poor and a score of 3, excellent image quality). Anatomic variants of the arterial, venous, portal venous, and biliary structures were identified. RESULTS: Image quality was diagnostic in all examinations except for 4 of 30 MRA data sets. Intrahepatic biliary structures, especially with regard to the intrahepatic bile ducts of 2nd and 3rd order could be identified with significantly increased image quality than in conventional T2-weighted MRC sequences (P = 0.005 and P = 0.035). A high percentage rate of anatomic variants regarding the biliary, arterial, venous, and portal venous anatomy was found. CONCLUSION: This protocol allows the evaluation of liver donors especially with regard to the biliary structures. However, the depiction of the arterial anatomy requires further technical developments.

[Liver metastases of neuroendocrine tumors]. / Lebermetastasen neuroendokriner Tumoren.

Neuroendocrine liver metastases (NELM) are very heterogeneous with respect to the clinical presentation and the prognosis. The treatment of NELMs requires a multidisciplinary approach and patients with NELM should be referred to a specialized center. When possible, the resection of NELMs provides the best long-term results. The general selection criteria for liver resection include an acceptable general physical condition for a large liver operation, tumors with a favorable differentiation grade 1 or 2, a lack of extrahepatic lesions, a sufficient residual liver volume and the possibility to resect at least 70% of the metastases. Supplementary treatment, including simultaneous liver ablation, are generally safe and can increase the number of patients who can be considered for surgery. For patients with resectable NELM, the resection of the primary tumor is recommended either in a 2-stage or combined procedure. In selected patients with nonresectable NELM a liver transplantation can be carried out, which can be associated with excellent long-term results.