The role of apoptotic bone marrow cells in activation of liver regeneration

Objective: using an adoptive transfer model to study the cellular mechanisms involved in the formation of the initial stage of liver regeneration during intraperitoneal injection of a healthy recipient with apoptotic bone marrowderived mononuclear cells (BM-MNCs) from a donor after extended liver resection.Materials and methods. Male Wistar rats (n = 40) were used to create a model of adoptive transfer of apoptotic BM-MNCs (a-BM-MNCs) taken from the donor after extended liver resection to a healthy recipient. During the experiments, the animals were divided into five groups. Four experimental groups with intraperitoneal injection of the same doses to the recipient: freshly isolated BM-MNCs (group 1); BM-MNCs subjected to apoptosis for 48 hours by storage at t = 4–6 °C in phosphate-buffered saline (PBS) (group 2) or in a Custodiol HTK solution (group 3). In group 4, the animals were injected with PBS after storing BM-MNCs in it. The control animals were animals injected with saline (group 5). For selection of effective modes of apoptosis induction, BM-MNCs stained with 7AAD after incubation in solutions were analyzed by flow cytometry. Targeted transfer of regenerative signals to the recipient was assessed by the mitotic activity of hepatocytes in the liver and tubular epithelium in the kidneys, as well as by the intensity of microstructural changes in the liver 24, 48 and 72 hours after injection of the studied material.Results. BMC incubation in PBS and HTK for 48 hours at t = 4–6 °C provides the most effective accumulation of a-BM-MNCs in early apoptosis. It was shown that a-BM-MNCs retain the ability to target-focused transmission of regulatory signals to the liver supported by autophagy process during adoptive transfer. It was established that a-BM-MNCs (groups 2 and 3) in comparison to native BM-MNCs (group 1) at adoptive transfer increased the regenerative potential of the liver due to pronounced increase in the activity of autophagy processes and directed infiltration of immunomodulatory mononuclear cells in the liver.Conclusion. a-BM-MNCs create a stronger basis for development and implementation of a targeted and effective regeneration program by enhancing autophagy processes and immunomodulatory effect on mononuclear cells, which are regenerative signal carriers.

Vascular Resection for Intrahepatic Cholangiocarcinoma: Current Considerations

Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 10% of all primary liver cancers. Surgery is the only potentially curative treatment, even in cases of macrovascular invasion. Since resection offers the only curative chance, even extended liver resection combined with complex vascular or biliary reconstruction of the surrounding organs seems justified to achieve complete tumour removal. In selected cases, the major vascular resection is the only change to try getting the cure. The best results are achieved by the referral centre with a wide experience in complex liver surgery, such as ALPPS procedure, IVC resection, and ante-situ and ex-situ resections. However, despite aggressive surgery, tumour recurrence occurs frequently and long-term oncological results are very poor. This suggests that significant progress in prognosis cannot be expected by surgery alone. Instead, multimodal treatment including neoadjuvant chemotherapy, radiotherapy, and subsequent adjuvant treatment for iCCA seem to be necessary to improve results.

Current Surgical Management of Peri-Hilar and Intra-Hepatic Cholangiocarcinoma

Cholangiocarcinoma accounts for approximately 10% of all hepatobiliary tumors and represents 3% of all new-diagnosed malignancies worldwide. Intrahepatic cholangiocarcinoma (i-CCA) accounts for 10% of all cases, perihilar (h-CCA) cholangiocarcinoma represents two-thirds of the cases, while distal cholangiocarcinoma accounts for the remaining quarter. Originally described by Klatskin in 1965, h-CCA represents one of the most challenging tumors for hepatobiliary surgeons, mainly because of the anatomical vascular relationships of the biliary confluence at the hepatic hilum. Surgery is the only curative option, with the goal of a radical, margin-negative (R0) tumor resection. Continuous efforts have been made by hepatobiliary surgeons in order to achieve R0 resections, leading to the progressive development of aggressive approaches that include extended hepatectomies, associating liver partition, and portal vein ligation for staged hepatectomy, pre-operative portal vein embolization, and vascular resections. i-CCA is an aggressive biliary cancer that arises from the biliary epithelium proximal to the second-degree bile ducts. The incidence of i-CCA is dramatically increasing worldwide, and surgical resection is the only potentially curative therapy. An aggressive surgical approach, including extended liver resection and vascular reconstruction, and a greater application of systemic therapy and locoregional treatments could lead to an increase in the resection rate and the overall survival in selected i-CCA patients. Improvements achieved over the last two decades and the encouraging results recently reported have led to liver transplantation now being considered an appropriate indication for CCA patients.

CT-Based Prediction of Liver Function and Post-PVE Hypertrophy Using an Artificial Neural Network

Background: This study aimed to evaluate whether hypertrophy after portal vein embolization (PVE) and maximum liver function capacity (LiMAx) are predictable by an artificial neural network (ANN) model based on computed tomography (CT) texture features. Methods: We report a retrospective analysis on 118 patients undergoing preoperative assessment by CT before and after PVE for subsequent extended liver resection due to a malignant tumor at RWTH Aachen University Hospital. The LiMAx test was carried out in a subgroup of 55 patients prior to PVE. Associations between CT texture features and hypertrophy as well as liver function were assessed by a multilayer perceptron ANN model. Results: Liver volumetry showed a median hypertrophy degree of 33.9% (16.5–60.4%) after PVE. Non-response, defined as a hypertrophy grade lower than 25%, was found in 36.5% (43/118) of the cases. The ANN prediction of the hypertrophy response showed a sensitivity of 95.8%, specificity of 44.4% and overall prediction accuracy of 74.6% (p < 0.001). The observed median LiMAx was 327 (248–433) μg/kg/h and was strongly correlated with the predicted LiMAx (R2 = 0.89). Conclusion: Our study shows that an ANN model based on CT texture features is able to predict the maximum liver function capacity and may be useful to assess potential hypertrophy after performing PVE.

Extended liver resection in mice: state of the art and pitfalls—a systematic review

Background Rodent models of liver resection have been used to investigate and evaluate the liver’s complex physiology and pathology since 1931. First documented by Higgins and Anderson, such models were created to understand liver regeneration mechanisms to improve outcomes in patients undergoing extensive liver resection for liver cancer or other underlying liver diseases. Methods A systematic search was conducted using Pubmed, gathering publications up to January 2019, which engaged with the mouse model of extended liver resection as a method itself. The results of this search were filtered according to their language, novelty, and relevancy. Results The Boolean search found 3741 articles on Pubmed, with 3130 publications remaining when filtered by language and the presence of a full text. In total, 21 of these publications examined the key themes of the animal model described. The mortality varied from 0 to 50% depending on the surgeon's experience and the resection method. The liver resection was mainly performed with classic sutures (14 out of 21 publications) and isoflurane was used for anaesthesia (10 out of 21 publications) in combination with analgesics (buprenorphine or ketamine/xylazine). The most used mouse strain was C57BL/6 (7 of 21 publications) which was on average 11 weeks old with a weight of 23 g. Conclusion Through the overview, laid out in the selected publications, this paper reviews the shift of the extended liver resection model from rat to the mouse, describes the state of the art in the experimental setting, and discusses the possible limitations and pitfalls. Clearly, the extended liver resection in mice is a reproducible, practical and easy to learn method.