AI-based digital histopathology for perihilar cholangiocarcinoma: A step, not a jump.

Introduction: Perihilar cholangiocarcinoma (PHCC) is a rare malignancy with limited survival prediction accuracy. Artificial intelligence (AI) and digital pathology advancements have shown promise in predicting outcomes in cancer. We aimed to improve prognosis prediction for PHCC by combining AI-based histopathological slide analysis with clinical factors. Methods: We retrospectively analyzed 317 surgically treated PHCC patients (January 2009-December 2018) at the University Hospital of Essen. Clinical data, surgical details, pathology, and outcomes were collected. Convolutional neural networks (CNN) analyzed whole-slide images. Survival models incorporated clinical and histological features. Results: Among 142 eligible patients, independent survival predictors were tumor grade (G), tumor size (T), and intraoperative transfusion requirement. The CNN-based model combining clinical and histopathological features demonstrates proof of concept in prognosis prediction, limited by histopathological complexity and feature extraction challenges. However, the CNN-based model generated heatmaps assisting pathologists in identifying areas of interest. Conclusion: AI-based digital pathology showed potential in PHCC prognosis prediction, though refinement is necessary for clinical relevance. Future research should focus on enhancing AI models and exploring novel approaches to improve PHCC patient prognosis prediction.

Preoperative Computed Tomography Volumetry and Graft Weight Estimation of Left Lateral Segment in Pediatric Living Donor Liver Transplant.

OBJECTIVES: Liver volumetry based on a computed tomography scan is widely used to estimate liver volume before any liver resection, especially before living donorliver donation. The 1-to-1 conversion rule for liver volume to liver weight has been widely adopted; however, debate continues regarding this approach. Therefore, we analyzed the relationship between the left-lateral lobe liver graft volume and actual graft weight. MATERIALS AND METHODS: This study retrospectively included consecutive donors who underwent left lateral hepatectomy for pediatric living donor liver transplant from December 2008 to September 2020. All donors were healthy adults who met the evaluation criteria for pediatric living donor liver transplant and underwent a preoperative contrast-enhanced computed tomography scan. Manual segmentation of the leftlateral liverlobe for graft volume estimation and intraoperative measurement of an actual graft weight were performed. The relationship between estimated graft volume and actual graft weight was analyzed. RESULTS: Ninety-four living liver donors were included in the study. The mean actual graft weight was ~283.4 ± 68.5 g, and the mean graft volume was 244.9 ± 63.86 mL. A strong correlation was shown between graft volume and actual graft weight (r = 0.804; P < .001). Bland-Altman analysis revealed an interobserver agreement of 38.0 ± 97.25, and intraclass correlation coefficient showed almost perfect agreement(r = 0.840; P < .001). The conversion formula for calculating graft weight based on computed tomography volumetry was determined based on regression analysis: 0.88 × graft volume + 41.63. CONCLUSIONS: The estimation of left liver graft weight using only the 1-to-1 rule is subject to measurable variability in calculated graft weights and tends to underestimate the true graft weight. Instead, a different, improved conversion formula should be used to calculate graft weight to more accurately determine donor graft weight-to-recipient body weightratio and reduce the risk of underestimation of liver graft weightin the donor selection process before pediatric living donor liver transplant.

Transplantation for Primary Sclerosing Cholangitis: Outcomes and Recurrence.

Primary sclerosing cholangitis (PSC) is characterized by inflammation of the whole bile duct system. Liver transplantation is only approved as a curative treatment when it comes to end-stage liver disease. The aim of our study was to assess morbidity, survival rates and PSC recurrence and the impact of donor characteristics in long-term follow-up. This was an IRB-approved retrospective study. A total of 82 patients were identified who were transplanted between January 2010 and December 2021 for PSC. Among these patients, 76 adult liver transplant PSC patients and their corresponding donors were analyzed. Three pediatric cases and three adult patients with a follow-up within <1 year were excluded from further analysis. Median (range) age was 47 years (18-70) with a median (range) lab-MELD of 16 (7-40). Median (range) ICU and hospital stays were 4.6 days (0-147) and 21 days (1-176), respectively. The majority of patients suffered from Crohn's disease or ulcerative colitis as a concomitant comorbidity (65.8%). The ten-year survival rate was 74.6%. A significantly lower lab-MELD score was identified in patients surviving for > 10 years (15 vs. 22, p = 0.004). Most patients (65%) passed in the first year following transplantation, with primary non-function (PNF), sepsis and arterial thrombosis being the most common causes of death. Donor characteristics did not affect patient survival. Patients with PSC show excellent 10-year survival rates. While the lab-MELD score significantly affected long term outcomes, donor characteristics did not affect survival rates.

Fully automated preoperative liver volumetry incorporating the anatomical location of the central hepatic vein.

The precise preoperative calculation of functional liver volumes is essential prior major liver resections, as well as for the evaluation of a suitable donor for living donor liver transplantation. The aim of this study was to develop a fully automated, reproducible, and quantitative 3D volumetry of the liver from standard CT examinations of the abdomen as part of routine clinical imaging. Therefore, an in-house dataset of 100 venous phase CT examinations for training and 30 venous phase ex-house CT examinations with a slice thickness of 5 mm for testing and validating were fully annotated with right and left liver lobe. Multi-Resolution U-Net 3D neural networks were employed for segmenting these liver regions. The Sørensen-Dice coefficient was greater than 0.9726 ± 0.0058, 0.9639 ± 0.0088, and 0.9223 ± 0.0187 and a mean volume difference of 32.12 ± 19.40 ml, 22.68 ± 21.67 ml, and 9.44 ± 27.08 ml compared to the standard of reference (SoR) liver, right lobe, and left lobe annotation was achieved. Our results show that fully automated 3D volumetry of the liver on routine CT imaging can provide reproducible, quantitative, fast and accurate results without needing any examiner in the preoperative work-up for hepatobiliary surgery and especially for living donor liver transplantation.

The Edge of Unknown: Postoperative Critical Care in Liver Transplantation.

Perioperative care of patients undergoing liver transplantation (LT) is very complex. Metabolic derangements, hypothermia, coagulopathy and thromboses, severe infections, and graft dysfunction can affect outcomes. In this manuscript, we discuss several perioperative problems that can be encountered in LT recipients. The authors present the most up-to-date information regarding predicting and treating hemodynamic instability, coagulation monitoring and management, postoperative ventilation strategies and early extubation, management of infections, and ESLD-related pulmonary complications. In addition, early post-transplant allograft dysfunction will be discussed.

Therapy of pyogenic liver abscess with a primarily unknown cause.

PURPOSE: Pyogenic liver abscess (PLA) is a collection of pus in the liver, often without a known direct cause. There is discord on the best diagnostic and therapeutic strategy. We aimed to examine these questions in our patient cohort. METHODS: A total of 66 out of 309 patients with PLA at our tertiary referral center between 2012 and 2020 had a primarily unknown cause. We analyzed PLA configuration, comorbidities, and whether an underlying cause could be found later. Therapy was sorted by antibiotics alone, percutaneous drainage, and primary surgery. Success was assessed by a change of initial therapy, in-hospital mortality, and mean hospital stay. RESULTS: Overall mortality was 18%; in 55%, a causative condition could be found. CRP, GGT, size, and multiple localization go along with higher mortality. Antibiotics alone had a failure rate of 82%. Percutaneous drainage was successful in 70% of cases. Surgery was mainly reserved for failed previous non-surgical treatment and had in-hospital mortality of 12%. CONCLUSIONS: PLA goes along with high mortality. In the majority of all patients, a causative condition can be identified by detailed diagnostics. Percutaneous drainage together with antibiotics is the therapy of choice and is successful in 70% of cases. If drainage is insufficient or impossible, surgery is an effective alternative.

Balancing Outcome vs. Urgency in Modern Liver Transplantation.

Background: Current allocation mechanisms for liver transplantation (LT) overemphasize emergency, leading to poorer longtime outcomes. The utility was introduced to recognized outcomes in allocation. Recently, Molinari proposed a predictive outcome model based on recipient data. Aims: The aims of this study were to validate this model and to combine it with the utility to emphasize outcome in allocation. Methods: We retrospectively analyzed 734 patients who were transplanted between January 2010 and December 2019. Points were assigned as in Molinari's model and the score sum was correlated with observed 90-day mortality. The utility was calculated as the product of 1-year survival times 3-month mortality on the waiting list. The weighting of different compounds was introduced, and utility curves were calculated. Model for End-Stage Liver Disease (MELD) scores according to maximal utility were determined. Results: In total, 120 patients (16.3%) had died within 90 days after LT. Higher MELD score, obesity, and hemodialysis prior to LT were confirmed risk factors. Overall survival was 83.8 and 77.4% after 90 days and 12 months, respectively. General utility culminated at MELD scores >35 in the overall population. Emphasizing the outcome shifted the maximal utility to lower MELD scores depending on Molinari scores. Conclusions: Emphasizing outcome, at least in certain recipient risk categories, might improve the longtime outcomes and might be integrated into allocation models.

HTK-N as a new preservation solution for human kidney preservation: Results of a pilot randomized controlled clinical phase II trial in living donor transplantation.

BACKGROUND: HTK-N was developed based on the traditional HTK preservation solution, resulting in stronger protection against reactive oxygen species as well as better tolerance to hypothermia and ischemia. Aim of the present study was to compare HTK-N to HTK in clinical kidney transplantation demonstrating safety and non-inferiority. METHODS: We performed a randomized controlled single blinded clinical phase II trial in patients undergoing living donor kidney transplantation. After retroperitoneoscopic nephrectomy kidneys were either perfused and stored with classical HTK solution or the new HTK-N solution. Primary endpoint was the glomerular filtration rate (eGFR according to CKD EPI) 3 months after transplantation. Secondary endpoints included graft and patient survival beside others. RESULTS: The study included 42 patients, of which 22 were randomized in the HTK-N group and 20 in the HTK group. The primary end point showed a mean eGFR of 55.4 ± 14.0 ml/min/1.73 m2 in the HTK group compared to a GFR of 57.2 ± 16.7 ml/min/m2 in the HTK-N group (P = .72). Regarding secondary endpoints, there were no apparent differences. Posttransplant graft and patient survival was 100%. CONCLUSION: This study is the first clinical application of HTK-N for kidney preservation and demonstrates non-inferiority compared to HTK in the setting of living donor kidney transplantation.

Enzymatic liver function measured by LiMAx is superior to current standard methods in predicting transplant-free survival after TIPS implantation.

Transjugular intrahepatic portosystemic shunt (TIPS) is one of the main treatment options in patients with decompensated liver cirrhosis but is still associated with partly severe complications. For adequate patient selection, prognostic parameters are of crucial importance. The liver maximum capacity (LiMAx) breath test measures enzymatic liver function and could potentially represent an efficient prognostic marker. We therefore aimed to assess the role of LiMAx in predicting survival of TIPS patients in a prospective analysis. LiMAx was performed for patients who underwent TIPS implantation between October 2016 and February 2018. Associations with transplant-free survival after 24 weeks were assessed by logistic regression. A total number of 30 patients were included, of whom seven received liver transplantation (N = 2) or died (N = 5) during follow-up. LiMAx values after (P = 0.01, OR = 1.24, 95% CI = 1.04-1.47) and before (P = 0.03, OR 1.21, 95% CI = 1.02-1.43) TIPS implantation and MELD score (P = 0.03, OR = 0.79, 95% CI = 0.63-0.98) were significantly associated with transplant-free survival according to univariate logistic regression. In AUROC analysis, LiMAx at day one after TIPS (sensitivity 85.7%, specificity 78.3%, AUROC 0.85, cut-off ≤ 165 µg/kg/h), LiMAx value at the day before TIPS (sensitivity 100%, specificity 73.9%, AUROC 0.82, cut-off ≤ 205 µg/kg/h) and MELD score (sensitivity 71.4%, specificity 73.9%, AUROC 0.82, cut-off ≥ 15) had the highest prognostic accuracy. LiMAx values prior and after TIPS procedure seem to be good prognostic parameters regarding prediction of transplant-free survival of patients undergoing TIPS implantation.

Long-term Outcomes After Controlled Oxygenated Rewarming of Human Livers Before Transplantation.

Controlled oxygenated rewarming (COR) has been shown to be a feasible and safe method in clinical practice and to reduce peak serum transaminases after liver transplantation. This study aimed to demonstrate further clinical experience of this method of now 18 clinical liver transplantations utilizing COR and demonstrate the long-term results. METHODS: In this extended series of 18 patients, cold-stored livers were subjected to machine-assisted slow COR for ≈120 minutes before transplantation. A cohort of 178 patients transplanted during the same period with similar clinical characteristics were used for comparison of key outcomes. RESULTS: All livers were perfused in accordance to the COR protocol without incidences and transplanted successfully. Early allograft dysfunction was observed in 2 (11.1%) cases after COR. Liver elasticity measurements indicated normal healthy liver parenchyma at the last follow-up. Graft survival demonstrated excellent outcomes after COR. The 1-, 3-, and 5-year patient survival rates were 100%, 100%, and 93.8% compared with 84.5%, 82.0%, and 75.8% in the control group (P = 0.12). CONCLUSIONS: The present study demonstrates excellent clinical outcomes after COR before liver transplantation. Comparison with a control cohort shows superiority of graft survival. Further evidence is needed to assess this promising method to improve organ preservation, finally.

Long-term outcome of third, fourth and fifth kidney transplantation: technical aspects and immunological challenges.

BACKGROUND: The number of patients on waiting lists for repeated kidney transplantation has increased. However, retransplanted patients have a greater surgical and immunological risk than first-time kidney recipients. METHODS: We retrospectively analysed all kidney recipients that underwent third, fourth or fifth kidney transplantation (Group 3+) at the University Hospital Essen, Essen, Germany from October 1973 to January 2017. A historical cohort of recipients retransplanted with a second kidney (Group 2) served as the control. Donor and recipient demographic data, cold ischaemia time (CIT), warm ischaemia time, overall operation time and methods, transplantectomy of previous kidney grafts, incidence of surgical and immunological complications as well as patient- and death-censored survival were analysed. RESULTS: We identified 108 recipients transplanted with the third, fourth or fifth renal allograft. Patients with more than one transplantation had significantly higher surgical risk due to atherosclerosis (P = 0.002) and higher immunological risk due to higher panel reactive antibody levels preoperatively (current panel reactive antibody P = 0.004; highest panel reactive antibody value P = 0.0001). Group 3+ patients had more often undergone previous transplant nephrectomy (P = 0.0001). There was a significant difference in CIT (P = 0.009), overall operative time (P = 0.0001) and post-transplantation thrombotic events (P = 0.02). We could not demonstrate any differences in graft and patient survival. CONCLUSION: Third, fourth and fifth transplant recipients are a high-risk patient cohort. Our results suggest that patient survival after more than three renal transplantations is similar to that of second graft recipients. This supports the concept of repeated kidney retransplantations.

Analysis of Data from the Oxygen Persufflation in Liver Transplantation (OPAL) Study to Determine the Role of Factors Affecting the Hepatic Microcirculation and Early Allograft Dysfunction.

BACKGROUND Adequate microcirculatory perfusion is essential for the provision of oxygen to the liver following transplantation. Data from the Oxygen Persufflation in Liver Transplantation (OPAL) study (ISRCTN00167887) were analyzed from liver transplants performed at a single center to determine the role of factors affecting the hepatic microcirculation and early allograft dysfunction (EAD). MATERIAL AND METHODS Retrospective data from 116 patients from the Oxygen Persufflation as Adjunction in Liver Transplantation (OPAL) study who underwent liver transplantation at a single center were analyzed. Oxygen saturation of hemoglobin (SO2), relative capillary hemoglobin concentration (rHb), relative tissue blood flow (rBF) using laser Doppler flow measurements, and the Oxygen-to-See (O2C) spectrometry were measured and with post-transplant allograft function were analyzed using univariate and multivariate logistic regression statistics. RESULTS Livers donors had a median donor risk index of 1.8. Most liver transplant recipients were men (60.3%), with a median age of 54 years (IQR, 23-68 years). Mean post-transplant 3-month survival was 90.5%. The EAD rate was 22.4%, the median SO2 was 78% (IQR, 29.5-95.8%), the median rHb was 55.6 AU (IQR, 16.8-74.8 AU), and the median rBF was 110.1 AU (IQR, 35.8-406.8 AU). Multivariate logistic regression analysis showed that tissue SO2 (p=0.01), body mass index (BMI) of the transplant recipient (p=0.002), serum alanine transaminase (ALT) of the donor (p=0.02), and portal blood flow (p=0.01) were predictive factors for EAD. CONCLUSIONS Non-invasive investigations of the liver microcirculation and hemoglobin oxygenation were shown to be predictive factors for EAD following liver transplantation.

Liver maximum capacity (LiMAx) test as a helpful prognostic tool in acute liver failure with sepsis: a case report.

BACKGROUND: Acute liver failure (ALF) is a life-threatening entity particularly when infectious complications worsen the clinical course. Urgent liver transplantation (LT) is frequently the only curative treatment. However, in some cases, recovery is observed under conservative treatment. Therefore, prognostic tools for estimating course of the disease are of great clinical interest. Since laboratory parameters sometimes lack sensitivity and specificity, enzymatic liver function measured by liver maximum capacity (LiMAx) test may offer novel and valuable additional information in this setting. CASE PRESENTATION: We here report the case of a formerly healthy 20-year old male caucasian patient who was admitted to our clinic for ALF of unknown origin in December 2017. Laboratory parameters confirmed the diagnosis with an initial MELD score of 28 points. Likewise, enzymatic liver function was significantly impaired with a value of 147 [> 315] µg/h/kg. Clinical and biochemical analyses for viral-, autoimmune-, or drug-induced hepatitis were negative. Liver synthesis parameters further deteriorated reaching a MELD score of 40 points whilst clinical course was complicated by septic pneumonia leading to severe hepatic encephalopathy grade III-IV, finally resulting in mechanical ventilation of the patient. Interestingly, although clinical course and laboratory data suggested poor outcome, serial LiMAx test revealed improvement of the enzymatic liver function at this time point increasing to 169 µg/h/kg. Clinical condition and laboratory data slowly improved likewise, however with significant time delay of 11 days. Finally, the patient could be dismissed from our clinic after 37 days. CONCLUSION: Estimating prognosis in patients with ALF is challenging by use of the established scores. In our case, improvement of enzymatic liver function measured by the LiMAx test was the first parameter predicting beneficial outcome in a patient with ALF complicated by sepsis.

Computed tomography donor liver volumetry before liver transplantation in infants ≤10 kg: does the estimated graft diameter affect the outcome?

AIM OF THE STUDY: Living donor liver transplantation (LDLT) is regularly performed in small-sized infants. Computed tomography (CT)-based donor liver volumetry is used to estimate the graft size. The aim of our study was to assess the results of CT liver volumetry and their impact on the clinical outcome after LDLT in extremely small-sized infants. PATIENTS AND METHODS: In this study, we included all patients with a body weight of ≤10 kg who underwent living related liver transplantation at our centre between January 2004 and December 2014. In all cases of LDLT, a preoperative CT scan of the donor liver was performed, and the total liver and graft volumes were calculated. The graft shape was estimated by measuring the ventro-dorsal (thickness), cranio-caudal, and transversal (width) diameter of segment II/III. We assessed the impact of CT donor liver volumetry and other risk factors on the outcome, defined as patient and graft survival. RESULTS: In the study period, a total of 48 living related liver transplantations were performed at our centre in infants ≤10 kg [20 male (42%), 28 female (58%)]. The mean weight was 7.3 kg (range 4.4-10 kg). Among the recipients, 33 (69%) received primary abdominal closure and 15 (31%) had temporary abdominal closure. The patient and graft survival rates were 85% and 81%, respectively. In CT volumetry, the mean estimated graft volume was 255 mL (range 140-485 mL) and the actual measured mean graft weight was 307 g (range 127-463 g). The mean ventro-dorsal diameter of segment II/III was 6.9 cm (range 4.3-11.2 cm), the mean cranio-caudal diameter was 9 cm (range 5-14 cm), and the mean width was 10.5 cm (range 6-14.7 cm). The mean graft-body weight ratio (GBWR) was 4.38% (range 1.41-8.04%). A high graft weight, a GBWR >4%, and a large ventro-dorsal diameter of segment II/III were risk factors for poorer patient survival. CONCLUSION: Preoperative assessment of the graft size is a crucial investigation before LDLT. For extremely small-sized recipients, not only the graft weight but also the graft shape seems to affect the outcome.

Liver Transplantation From Donors With a History of Malignancy: A Single-Center Experience.

BACKGROUND: The demand for transplantable organs exceeds donor organ supply. Transplantation of organs from donors with a history of malignancy remains controversial and the transmission of cancer in liver transplant recipients has not been sufficiently examined. METHODS: From 2002 until 2017, 83 livers from donors with a history of malignancy were transplanted at the University Hospital Essen, Germany. Donor and recipient data, type of malignancy, tumor-free interval at organ procurement, and follow-up data were analyzed. RESULTS: Nine different tumor sites (central nervous system [n = 27], genitourinary [n = 24], breast [n = 10], skin [n = 8], colorectal [n = 5], lung [n = 3], hemato-oncological [n = 3], thyroid [n = 2], and larynx [n = 1]) were detected in 83 donors. The majority (58%) of donors had tumor-free intervals of less than 5 years versus 19% of 6 to 10 years versus 23% over 10 years. The risk of tumor transmission from donors was assessed as low in 44 (53%), intermediate in 28 (34%), and high in 11 (13%) cases. During median follow-up of 19.9 (0-155) months, none of the recipients developed donor-transmitted malignancy. CONCLUSIONS: Liver transplantation with organs from donors with a medical history of malignancy is feasible, and the risk of donor-transmitted malignancy appears to be low in this single-center analysis. A careful selection of donors remains mandatory and can expand the donor pool.

The postoperative Model for End stage Liver Disease score as a predictor of short-term outcome after transplantation of extended criteria donor livers.

BACKGROUND: Recently, the postoperative Model for End stage Liver Disease score (POPMELD) was suggested as a definition of postoperative graft dysfunction and a predictor of outcome after liver transplantation (LT). AIM: The aim of the present study was to validate this concept in the context of extended criteria donor (ECD) organs. PATIENTS AND METHODS: Single-center prospectively collected data (OPAL study/01/11-12/13) of 116 ECD LTs were utilized. For each recipient, the Model for End stage Liver Disease (MELD) score was calculated for 7 postoperative days (PODs). The ability of international normalized ratio, bilirubin, aspartate aminotransferase, Donor Risk Index, a recent definition of early allograft dysfunction, and the POPMELD was compared to predict 90-day graft loss. Predictive abilities were compared by receiver operating characteristic curves, sensitivity and specificity, and positive and negative predictive values. RESULTS: The median Donor Risk Index was 1.8. In all, 60.3% of recipients were men [median age of 54 (23-68) years]. The median POD1-7 peak-aspartate aminotransferase value was 1052 (194-17 577) U/l. The rate of early allograft dysfunction was 22.4%. The 90-day graft survival was 89.7%. Out of possible predictors of the 90-day graft loss MELD on POD5 was the best predictor of outcome (area under the curve=0.84). A MELD score of 16 or more on POD5 predicted the 90-day graft loss with a specificity of 80.8%, a sensitivity of 81.8%, and a positive and negative predictive value of 31 and 97.7%. CONCLUSION: A MELD score of 16 or more on POD5 is an excellent predictor of outcome in ECD donor LT. Routine evaluation of POPMELD scores might support clinical decision-making and should be reported routinely in clinical trials.

Two and a Half Hours of Cardiopulmonary Resuscitation in a Deceased Brain Dead Donor before Liver Transplantation - A Good Idea to Accept?

The sequelae of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in organ donors potentially results in ischemic organ injury and graft dysfunction after transplantation. Thresholds of resuscitation times in brain dead liver donors have not been established so far. We report the case of a brain dead liver donor who experienced 2.5 hours of CPR whose liver was successfully transplanted. A 75-year-old male experienced CA and was treated by CPR with streptokinase application for 2.5 hours until stabilization of cardiac function. Brain death was diagnosed at the day of admission and organ donation carried out within 24 hours. The DRI was 2.2 with a CIT of 8.8 hours. The liver was transplanted into a 64-year-old recipient suffering from alcoholic liver cirrhosis and a MELD-score of 10 non representative for severity of disease. During follow up of 4 years ERCP and stenting was performed regularly for biliary anastomosis stenosis. The patient remained in a very good overall state of health without any signs of liver dysfunction. This case demonstrates that an extensive period of CPR is not an obligatory exclusion criterion for liver donation. Thresholds of CPR times as well as predictive factors in donors with CA should be established.