From morbidity reduction to cost-effectiveness: Enhanced recovery after surgery (ERAS) society recommendations in minimal invasive liver surgery.

PURPOSE: Minimal-invasive liver surgery (MILS) reduces surgical trauma and is associated with fewer postoperative complications. To amplify these benefits, perioperative multimodal concepts like Enhanced Recovery after Surgery (ERAS), can play a crucial role. We aimed to evaluate the cost-effectiveness for MILS in an ERAS program, considering the necessary additional workforce and associated expenses. METHODS: A prospective observational study comparing surgical approach in patients within an ERAS program compared to standard care from 2018-2022 at the Charité - Universitätsmedizin Berlin. Cost data were provided by the medical controlling office. ERAS items were applied according to the ERAS society recommendations. RESULTS: 537 patients underwent liver surgery (46% laparoscopic, 26% robotic assisted, 28% open surgery) and 487 were managed by the ERAS protocol. Implementation of ERAS reduced overall postoperative complications in the MILS group (18% vs. 32%, p = 0.048). Complications greater than Clavien-Dindo grade II incurred the highest costs (€ 31,093) compared to minor (€ 17,510) and no complications (€13,893; p < 0.001). In the event of major complications, profit margins were reduced by a median of € 6,640. CONCLUSIONS: Embracing the ERAS society recommendations in liver surgery leads to a significant reduction of complications. This outcome justifies the higher cost associated with a well-structured ERAS protocol, as it effectively offsets the expenses of complications.

FIRE-9 - PORT / AIO-KRK-0418: a prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of adjuvant/additive chemotherapy in patients with definitely-treated metastatic colorectal cancer.

BACKGROUND: Additive/adjuvant chemotherapy as concept after local treatment of colorectal metastases has not been proven to be successful by phase III trials. Accordingly, a standard of care to improve relapse rates and long-term survival is not established and adjuvant chemotherapy cannot be recommended as a standard therapy due to limited evidence in literature. The PORT trial aims to generate evidence that post-resection/ablation/radiation chemotherapy improves the survival in patients with metastatic colorectal cancer. METHODS: Patients to be included into this trial must have synchronous or metachronous metastases of colorectal cancer-either resected (R0 or R1) and/or effectively treated by ablation or radiation within 3-10 weeks before randomization-and have the primary tumor resected, without radiographic evidence of active metastatic disease at study entry. The primary endpoint of the trial is progression-free survival after 24 months, secondary endpoints include overall survival, safety, quality of life, treatments (including efficacy) beyond study participation, translational endpoints, and others. One arm of the study comprising 2/3 of the population will be treated for 6 months with modified FOLFOXIRI or modified FOLFOX6 (investigator´s choice, depending on the performance status of the patients but determined before randomization), while the other arm (1/3 of the population) will be observed and undergo scheduled follow-up computed tomography scans according to the interventional arm. DISCUSSION: Optimal oncological management after removal of colorectal metastases is unclear. The PORT trial aims to generate evidence that additive/adjuvant chemotherapy after definitive treatment of colorectal metastases improves progression free and overall survival in patients with colorectal cancer. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov ( NCT05008809 ) and EudraCT (2020-006,144-18).

The influence of the COVID-19 pandemic on surgical therapy and care: a cross-sectional study.

BACKGROUND: Due to the COVID-19 pandemic, an extensive reorganisation of healthcare resources was necessary-with a particular impact on surgical care across all disciplines. However, the direct and indirect consequences of this redistribution of resources on surgical therapy and care are largely unknown. METHODS: We analysed our prospectively collected standardised digital quality management document for all surgical cases in 2020 and compared them to the years 2018 and 2019. Periods with high COVID-19 burdens were compared with the reference periods in 2018 and 2019. RESULTS: From 2018 to 2020, 10,723 patients underwent surgical treatment at our centres. We observed a decrease in treated patients and a change in the overall patient health status. Patient age and length of hospital stay increased during the COVID-19 pandemic (p = 0.004 and p = 0.002). Furthermore, the distribution of indications for surgical treatment changed in favour of oncological cases and less elective cases such as hernia repairs (p < 0.001). Postoperative thromboembolic and pulmonary complications increased slightly during the COVID-19 pandemic. There were slight differences for postoperative overall complications according to Clavien-Dindo, with a significant increase of postoperative mortality (p = 0.01). CONCLUSION: During the COVID-19 pandemic we did not see an increase in the occurrence, or the severity of postoperative complications. Despite a slightly higher rate of mortality and specific complications being more prevalent, the biggest change was in indication for surgery, resulting in a higher proportion of older and sicker patients with corresponding comorbidities. Further research is warranted to analyse how this changed demographic will influence long-term patient care.

VolumetricOR: A New Approach to Simulate Surgical Interventions in Virtual Reality for Training and Education.

BACKGROUND: Surgical training is primarily carried out through observation during assistance or on-site classes, by watching videos as well as by different formats of simulation. The simulation of physical presence in the operating theatre in virtual reality might complement these necessary experiences. A prerequisite is a new education concept for virtual classes that communicates the unique workflows and decision-making paths of surgical health professions (i.e. surgeons, anesthesiologists and surgical assistants) in an authentic and immersive way. For this project, media scientists, designers and surgeons worked together to develop the foundations for new ways of conveying knowledge using virtual reality in surgery. MATERIALS AND METHOD: A technical workflow to record and present volumetric videos of surgical interventions in a photorealistic virtual operating room was developed. Situated in the virtual reality demonstrator called VolumetricOR, users can experience and navigate through surgical workflows as if they are physically present. The concept is compared with traditional video-based formats of digital simulation in surgical training. RESULTS: VolumetricOR let trainees experience surgical action and workflows (a) three-dimensionally, (b) from any perspective and (c) in real scale. This improves the linking of theoretical expertise and practical application of knowledge and shifts the learning experience from observation to participation. DISCUSSION: Volumetric training environments allow trainees to acquire procedural knowledge before going to the operating room and could improve the efficiency and quality of the learning and training process for professional staff by communicating techniques and workflows when the possibilities of training on-site are limited.

Ex vivo machine perfusion: current applications and future directions in liver transplantation.

BACKGROUND: Liver transplantation is the only curative treatment option for end-stage liver disease; however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool. PURPOSE: To present a systematic review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions. METHODS: A systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed. RESULTS: Twenty-one articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, eleven on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are twelve studies enrolled in the clinicaltrials.gov  registry, and these focus on use of ex vivo perfusion in extended criteria donors and declined organs. CONCLUSION: Ex vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.

Notch Signaling Pathway in Pancreatobiliary Tumors.

Background and objectives: The Notch signaling pathway plays an important role both in the development of the ductal systems of the pancreas and the bile ducts as well as in cancer development and progression. The aim of this study was to examine the expression of central proteins of the Notch signaling pathway in pancreatobiliary tumors and its influence on patient survival. Materials and Methods: We compared the receptors (Notch1, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas via immunohistochemistry and ImageJ software-assisted analysis. An Immunohistochemistry (IHC)-score was determined by the percentage and intensity of stained (positive) cells (scale 0-7) and normal and malignant tissue was compared. In the IHC results, patients' (gender, age) and tumor (TNM Classification of Malignant Tumors, Union Internationale contre le Cancer (UICC) stages, grading, and lymphangitic carcinomatosa) characteristics were correlated to patient survival. Results: For eCC, the expression of CD44 (p = 0.043, IHC-score 3.94 vs. 3.54) and for iCC, the expression of CD44 (p = 0.026, IHC-score 4.04 vs. 3.48) and Notch1 (p < 0.001, IHC-score 2.87 vs. 1.78) was significantly higher in the tumor compared to non-malignant tissue. For PDAC, the expression of ADAM17 (p = 0.008, IHC-score 3.43 vs. 1.73), CD44 (p = 0.012, IHC-score 3.64 vs. 2.27), Notch1 (p = 0.012, IHC-score 2.21 vs. 0.64), and Notch4 (p = 0.008, IHC-score 2.86 vs. 0.91) was significantly higher in the tumor tissue. However, none of the analyzed Notch-signaling related components showed an association to patient survival. Conclusion: A significant overexpression of almost all studied components of the Notch signaling pathway can be found in the tumor tissue, however, without a significant influence on patient survival. Therefore, further studies are warranted to draw conclusions on Notch pathway's relevance for patient survival.

Hospitalization Before Liver Transplantation Predicts Posttransplant Patient Survival: A Propensity Score-Matched Analysis.

In contrast to donor factors predicting outcomes of liver transplantation (LT), few suitable recipient parameters have been identified. To this end, we performed an in-depth analysis of hospitalization status and duration prior to LT as a potential risk factor for posttransplant outcome. The pretransplant hospitalization status of all patients undergoing LT between 2005 and 2016 at the Charité-Universitätsmedizin Berlin was analyzed retrospectively using propensity score matching. At the time of organ acceptance, 226 of 1134 (19.9%) recipients were hospitalized in an intensive care unit (ICU), 146 (12.9%) in a regular ward (RW) and 762 patients (67.2%) were at home. Hospitalized patients (RW and ICU) compared with patients from home showed a dramatically shorter 3-month survival (78.7% versus 94.4%), 1-year survival (66.3% versus 87.3%), and 3-year survival (61.7% versus 81.7%; all P < 0.001), whereas no significant difference was detected for 3-year survival between ICU and RW patients (61.5% versus 62.3%; P = 0.60). These results remained significant after propensity score matching. Furthermore, in ICU patients, but not in RW patients, survival correlated with days spent in the ICU before LT (1-year survival: 1-6 versus 7-14 days: 73.7% versus 60.5%, P = 0.04; 7-14 days versus >14 days, 60.5% versus 51.0%, P = 0.006). In conclusion, hospitalization status before transplantation is a valuable predictor of patient survival following LT.

[Declined Liver Grafts - Analysis of the German Donor Population from 2010 to 2018]. / Nicht transplantierte Spenderorgane ­ eine bundesweite Auswertung aller Organangebote für die Lebertransplantation von 2010 bis 2018.

BACKGROUND: The lack of suitable allografts limits the availability of liver transplantation in Germany. The quality of potentially available German donor livers has to date not been analyzed. METHODS: Analysis of all donors for potential liver transplantations reported to the Eurotransplant by the German Organ Transplantation Foundation from 2010 to 2018. Categorization of transplanted and discarded organs utilizing available histopathological reports and predefined extended criteria for organ donation. RESULTS: A total of 8594 livers were offered for transplantation, of which 15.2 % were discarded. During the analysis period the proportion of donor livers from extended criteria donors increased from 65 % to 70 % (p = 0.005). In 2018, 21.3 % of offered donor livers were discarded, more than half (56.4 %) of these organs came from donors meeting multiple extended criteria. Livers were significantly more likely to be not transplanted, when from donors of older age (> 65 years; 41 vs. 28 %), BMI > 30 kg/m2 (29 vs. 14 %) or elevated transaminase levels (all p < 0,001). CONCLUSION: Despite the consistent organ scarcity in Germany, a relevant amount of livers cannot be transplanted due to a multitude of organ quality limitations. This should stimulate the search for concepts such as normothermic ex vivo machine perfusion to evaluate, protect and potentially improve organ quality.

Improvement of Normothermic Ex Vivo Machine Perfusion of Rat Liver Grafts by Dialysis and Kupffer Cell Inhibition With Glycine.

Normothermic ex vivo liver machine perfusion might be a superior preservation strategy for liver grafts from extended criteria donors. However, standardized small animal models are not available for basic research on machine perfusion of liver grafts. A laboratory-scaled perfusion system was developed consisting of a custom-made perfusion chamber, a pressure-controlled roller pump, and an oxygenator. Male Wistar rat livers were perfused via the portal vein for 6 hours using oxygenated culture medium supplemented with rat erythrocytes. A separate circuit was connected via a dialysis membrane to the main circuit for plasma volume expansion. Glycine was added to the flush solution, the perfusate, and the perfusion circuit. Portal pressure and transaminase release were stable over the perfusion period. Dialysis significantly decreased the potassium concentration of the perfusate and led to significantly higher bile and total urea production. Hematoxylin-eosin staining and immunostaining for single-stranded DNA and activated caspase 3 showed less sinusoidal dilatation and tissue damage in livers treated with dialysis and glycine. Although Kupffer cells were preserved, tumor necrosis factor α messenger RNA levels were significantly decreased by both treatments. For proof of concept, the optimized perfusion protocol was tested with donation after circulatory death (DCD) grafts, resulting in significantly lower transaminase release into the perfusate and preserved liver architecture compared with baseline perfusion. In conclusion, our laboratory-scaled normothermic portovenous ex vivo liver perfusion system enables rat liver preservation for 6 hours. Both dialysis and glycine treatment were shown to be synergistic for preservation of the integrity of normal and DCD liver grafts.

Human Stem Cells Promote Liver Regeneration After Partial Hepatectomy in BALB/C Nude Mice.

BACKGROUND: Mesenchymal stem cells (MSCs) have been suggested to augment liver regeneration after surgically and pharmacologically induced liver failure. To further investigate this we processed human bone marrow-derived MSC according to good manufacturing practice (GMP) and tested those cells for their modulatory capacities of metabolic alterations and liver regeneration after partial hepatectomy in BALB/c nude mice. METHODS: Human MSCs were obtained by bone marrow aspiration of healthy donors as in a previously described GMP process. Transgenic GFP-MSCs were administered i.p. 24 h after 70% hepatectomy in BALB/c nude mice, whereas control mice received phosphate-buffered saline. Mice were sacrificed 2, 3, and 5 d after partial hepatectomy. Blood and organs were harvested and metabolic alterations as well as liver regeneration subsequently assessed by liver function tests, multianalyte profiling immunoassays, histology, and immunostaining. RESULTS: Hepatocyte and sinusoidal endothelial cell proliferation were significantly increased after partial hepatectomy in mice receiving MSC compared to control mice (Hepatocyte postoperative day 3, P < 0.01; endothelial cell postoperative day 5, P < 0.05). Hepatocyte fat accumulation correlated inversely with hepatocyte proliferation (r2 = 0.4064, P < 0.01) 2 d after partial hepatectomy, with mice receiving MSC being protected from severe fat accumulation. No GFP-positive cells could be detected in the samples. Serum levels of IL-6, HGF, and IL-10 were significantly decreased at day 3 in mice receiving MSC when compared to control mice (P < 0.05). Relative body weight loss was significantly attenuated after partial hepatectomy in mice receiving MSC (2 d and 3 d, both P < 0.001) with a trend toward a faster relative restoration of liver weight, when compared to control mice. CONCLUSIONS: Human bone marrow-derived MSC attenuate metabolic alterations and improve liver regeneration after partial hepatectomy in BALB/c nude mice. Obtained results using GMP-processed human MSC suggest functional links between fat accumulation and hepatocyte proliferation, without any evidence for cellular homing. This study using GMP-proceeded MSC has important regulatory implications for an urgently needed translation into a clinical trial.

Strategies based on organ decellularization and recellularization.

Transplantation is the only curative treatment option available for patients suffering from end-stage organ failure, improving their quality of life and long-term survival. However, because of organ scarcity, only a small number of these patients actually benefit from transplantation. Alternative treatment options are needed to address this problem. The technique of whole-organ decellularization and recellularization has attracted increasing attention in the last decade. Decellularization includes the removal of all cellular components from an organ, while simultaneously preserving the micro and macro anatomy of the extracellular matrix. These bioscaffolds are subsequently repopulated with patient-derived cells, thus constructing a personalized neo-organ and ideally eliminating the need for immunosuppression. However, crucial problems have not yet been satisfyingly addressed and remain to be resolved, such as organ and cell sources. In this review, we focus on the actual state of organ de- and recellularization, as well as the problems and future challenges.

Real world usability analysis of two augmented reality headsets in visceral surgery.

Recent developments in the field of augmented reality (AR) have enabled new use cases in surgery. Initial set-up of an appropriate infrastructure for maintaining an AR surgical workflow requires investment in appropriate hardware. We compared the usability of the Microsoft HoloLens and Meta 2 head mounted displays (HMDs). Fifteen medicine students tested each device and were questioned with a variant of the System Usability Scale (SUS). Two surgeons independently tested the devices in an intraoperative setting. In our adapted SUS, ergonomics, ease of use, and visual clarity of the display did not differ significantly between HMD groups. The field of view (FOV) was smaller in the Microsoft HoloLens than the Meta 2 and significantly more study subjects (80% vs. 13.3%; P < 0.001) felt limited through the FOV. Intraoperatively, decreased mobility due to the necessity of an AC adapter and additional computing device for the Meta 2 proved to be limiting. Object stability was rated superior in the Microsoft HoloLens than the Meta 2 by our surgeons and lead to increased use. In summary, after examination of the Meta 2 and the Microsoft HoloLens, we found key advantages in the Microsoft HoloLens which provided palpable benefits in a surgical setting.

Teburu-Open source 3D printable bioreactor for tissue slices as dynamic three-dimensional cell culture models.

Three-dimensional tissue cultures are important models for the study of cell-cell and cell-matrix interactions, as well as, to investigate tissue repair and reconstruction pathways. Therefore, we designed a reproducible and easy to handle printable bioreactor system (Teburu), that is applicable for different approaches of pathway investigation and targeted tissue repair using human tissue slices as a three-dimensional cell culture model. Here, we definitively describe Teburu as a controlled environment to reseed a 500-µm thick decellularized human liver slice using human mesenchymal stroma cells. During a cultivation period of eight days, Teburu, as a semi-open and low consumption system, was capable to maintain steady pH and oxygenation levels. Its combination with additional modules delivers an applicability for a wide range of tissue engineering approaches under optimal culture conditions.

The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism.

Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. CONCLUSION: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630).

Mixed Reality in Visceral Surgery: Development of a Suitable Workflow and Evaluation of Intraoperative Use-cases.

OBJECTIVE: The paper evaluates the application of a mixed reality (MR) headmounted display (HMD) for the visualization of anatomical structures in complex visceral-surgical interventions. A workflow was developed and technical feasibility was evaluated. SUMMARY OF BACKGROUND DATA: Medical images are still not seamlessly integrated into surgical interventions and, thus, remain separated from the surgical procedure.Surgeons need to cognitively relate 2-dimensional sectional images to the 3-dimensional (3D) during the actual intervention. MR applications simulate 3D images and reduce the offset between working space and visualization allowing for improved spatial-visual approximation of patient and image. METHODS: The surgeon's field of vision was superimposed with a 3D-model of the patient's relevant liver structures displayed on a MR-HMD. This set-up was evaluated during open hepatic surgery. RESULTS: A suitable workflow for segmenting image masks and texture mapping of tumors, hepatic artery, portal vein, and the hepatic veins was developed. The 3D model was positioned above the surgical site. Anatomical reassurance was possible simply by looking up. Positioning in the room was stable without drift and minimal jittering. Users reported satisfactory comfort wearing the device without significant impairment of movement. CONCLUSION: MR technology has a high potential to improve the surgeon's action and perception in open visceral surgery by displaying 3D anatomical models close to the surgical site. Superimposing anatomical structures directly onto the organs within the surgical site remains challenging, as the abdominal organs undergo major deformations due to manipulation, respiratory motion, and the interaction with the surgical instruments during the intervention. A further application scenario would be intraoperative ultrasound examination displaying the image directly next to the transducer. Displays and sensor-technologies as well as biomechanical modeling and object-recognition algorithms will facilitate the application of MR-HMD in surgery in the near future.

Bile: miRNA pattern and protein-based biomarkers may predict acute cellular rejection after liver transplantation.

CONTEXT: Bile rather than blood depicts the local inflammation in the liver and may improve prediction and diagnosis of acute cellular rejection (ACR) after liver transplantation (OLT). METHODS: Secretome and miRNAs were analyzed during the first two weeks and on clinical suspicion of ACR in the bile of 45 OLT recipients. RESULTS: Levels of CD44, CXCL9, miR-122, miR-133a, miR-148a and miR-194 were significantly higher in bile of patients who developed ACR within the first 6 months after OLT and during ACR. CONCLUSION: Analysis of secretome and miRNA in bile could improve our understanding of the local inflammatory process during rejection.

Increased lipogenesis in spite of upregulated hepatic 5'AMP-activated protein kinase in human non-alcoholic fatty liver.

AIMS: Molecular adaptations in human non-alcoholic fatty liver disease (NAFLD) are incompletely understood. This study investigated the main gene categories related to hepatic de novo lipogenesis and lipid oxidation capacity. METHODS: Liver specimens of 48 subjects were histologically classified according to steatosis severity. In-depth analyses were undertaken using real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Lipid profiles were analyzed by gas chromatography/flame ionization detection, and effects of key fatty acids were studied in primary human hepatocytes. RESULTS: Real-time polymerase chain reaction, immunoblotting, and immunohistochemistry indicated 5'AMP-activated protein kinase (AMPK) to be increased with steatosis score ≥ 2 (all P < 0.05), including various markers of de novo lipogenesis and lipid degradation (all P < 0.05). Regarding endoplasmic reticulum stress, X-Box binding protein-1 (XBP1) was upregulated in steatosis score ≥ 2 (P = 0.029) and correlated with plasma palmitate (r = 0.34; P = 0.035). Palmitate incubation of primary human hepatocytes increased XBP1 and downstream stearoyl CoA desaturase-1 mRNA expression (both P < 0.05). Moreover, plasma and liver tissue exposed a NAFLD-related lipid profile with reduced polyunsaturated/saturated fatty acid ratio, increased palmitate and palmitoleate, and elevated lipogenesis and desaturation indices with steatosis score ≥ 2 (all P < 0.05). CONCLUSION: In humans with advanced fatty liver disease, hepatic AMPK protein is upregulated, potentially in a compensatory manner. Moreover, pathways of lipid synthesis and degradation are co-activated in subjects with advanced steatosis. Palmitate may drive lipogenesis by activating XBP1-mediated endoplasmic reticulum stress and represent a target for future dietary or pharmacological intervention.

Predictive factors for extrahepatic recurrence of hepatocellular carcinoma following liver transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) in patients treated with liver transplantation (LT) is associated with diminished survival. Particularly, extrahepatic localization of HCC recurrence contributes to poor prognosis. PATIENTS AND METHODS: Clinicopathological data of patients who underwent LT for HCC between 1989 and 2010 in a high-volume transplant center were retrospectively evaluated, and predictors of extrahepatic recurrence were identified. RESULTS: Three hundred and sixty-four patients underwent LT for HCC. After a median follow-up time of 78 months, 93 patients (25%) were diagnosed with a recurrence. Median time to recurrence was 19 months. Recurrence was located exclusively in the liver in 19 cases (20%), and 74 patients (80%) had extrahepatic recurrence. Factors associated with extrahepatic recurrence in multivariate analysis included HCC beyond the Milan criteria (p < 0.0001) and the presence of macrovascular tumor invasion (p = 0.035). In patients with HCC beyond the Milan criteria who developed a recurrence (N = 73), macrovascular invasion was the only positive predictor of extrahepatic recurrence in multivariate analysis (p < 0.0001). In patients with HCC within the Milan criteria who recurred after LT (N = 20), DNA-index >1.5 (p = 0.013) was the only predictive factor for extrahepatic recurrence in multivariate analysis. CONCLUSIONS: Advanced HCC beyond the Milan criteria and the presence of macrovascular invasion are associated with an increased risk for extrahepatic recurrence and are currently considered as relative contraindications to LT. In patients with HCC within the Milan criteria, the DNA-index represents a valuable prognostic marker for the development of extrahepatic recurrence and may support the selection of patients for intensified postoperative tumor surveillance.

microRNA signatures in peripheral blood fail to detect acute cellular rejection after liver transplantation.

OBJECTIVE: We investigated whether microRNA signatures in whole blood samples are associated with acute cellular rejection (ACR) after liver transplantation. MATERIALS AND METHODS: Blood samples were collected using Paxgene technology and analyzed by microarrays and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: microRNA signatures failed to distinguish between 19 patients with ACR and 16 controls. Let-7b-5p and let-7c were upregulated in a subgroup of patients with ACR during the 6th and 7th postoperative days but failed in an independent validation of 20 patients. CONCLUSION: microRNA signatures in whole blood processed by Paxgene technology are not suited for the detection of ACR after liver transplantation.