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Objective: The aim of this study was to assess the impact of postoperative hypophosphatemia on liver regeneration after major liver surgery in the scenario of Associating Liver Partition with Portal vein ligation for Staged hepatectomy (ALPPS) and living liver donation (LLD). Background: Hypophosphatemia has been described to reflect the metabolic demands of regenerating hepatocytes. BothALPPS and LLDare characterized by an exceptionally strong liver regeneration and may be of particular interest in the context of posthepatectomy hypophosphatemia. Methods: Serumphosphate changes within the first 7 postoperative days after ALPPS (n=61) and LLD (n=54) were prospectively assessed and correlated with standardized volumetry after 1 week. In a translational approach, postoperative phosphate changes were investigated in mice and in vitro. Results: After ALPPS stage 1 and LLD, serum phosphate levels significantly dropped from a preoperative median of 1.08 mmol/L [interquartile range (IQR) 0.92--1.23] and 1.07 mmol/L (IQR 0.91--1.21) to a postoperative median nadir of 0.68 and 0.52 mmol/L, respectively. A pronounced phosphate drop correlated well with increased liver hypertrophy (P< 0.001). Patients with a low drop of phosphate showed a higher incidence of posthepatectomy liver failure after ALPPS (7% vs 31%, P=0.041). Like in humans, phosphate drop correlated significantly with degree of hypertrophy in murine ALPPS and hepatectomy models (P<0.001). Blocking phosphate transporter (Slc20a1) inhibited cellular phosphate uptake and hepatocyte proliferation in vitro. Conclusion: Phosphate drop after hepatectomy is a direct surrogate marker for liver hypertrophy. Perioperative implementation of serum phosphate analysis has the potential to detect patients with insufficient regenerative capacity at an early stage. [ABSTRACT FROM AUTHOR]

Only a few decades ago, the opinion that colorectal liver metastases were a palliative diagnosis changed. In fact, previously, the prevailing view was strongly resistant against resecting colorectal liver metastases. Constant technical improvement of liver surgery and, much later, effective chemotherapy allowed for a successful wider application of surgery. The clinical use of portal vein embolization was the starting signal of regenerative liver surgery, where insufficient liver volume can be expanded to an extent where safe resection is possible. Today, a number of these techniques including portal vein ligation, associating liver partition and portal vein ligation for staged hepatectomy, and bi-embolization (portal and hepatic vein) can be successfully used to address an insufficient future liver remnant in staged resections. It turned out that the road to success is embedding surgery in a well-orchestrated oncological concept of controlling systemic disease. This concept was the prerequisite that meant liver transplantation could enter the treatment strategy for colorectal liver metastases, ending up with a 5-year overall survival of 80% in highly selected cases. In particular, techniques combining principles of 2-stage hepatectomy and liver transplantation, such as "resection and partial liver segment 2–3 transplantation with delayed total hepatectomy" (RAPID) are on the rise. These techniques enable the use of partial liver grafts with primarily insufficient liver volume. All this progress also prompted a number of innovative local therapies to address recurrences ultimately transferring colorectal liver metastases from instantly deadly into a chronic disease in some cases. [ABSTRACT FROM AUTHOR]

Postoperative pancreatic fistula remains an unsolved challenge after pancreatoduodenectomy. Important in this regard is the presence of a soft pancreatic texture which is a major risk factor. Advances in machine learning and texture analysis of medical images allow identification of features of parenchyma that are invisible to the human eye. The aim of this study was to investigate the potential of machine learning to predict postoperative pancreatic fistula based on preoperative, non-contrast-enhanced computed tomography. We screened a prospectively assessed database including all patients undergoing pancreatoduodenectomy at a tertiary center from 2008 until 2018 for patients based on the occurrence of postoperative pancreatic fistula. In total, 110 patients were included, consisting of 55 patients who developed a postoperative pancreatic fistula and 55 without postoperative pancreatic fistula. For machine learning-based texture analysis preoperative, non-contrast-enhanced computed tomography axial images were used. Machine learning results were tested using 10-fold cross validation. Previously validated clinical fistula risk scores (original and alternative fistula risk scores) served as reference tests. Both the original and the alternative fistula risk scores showed good discrimination between patients without and with postoperative pancreatic fistula (area under the curve 0.76 and 0.72, respectively). Machine learning-based texture analysis showed potential to detect histologic fibrosis (area under the curve 0.84, sensitivity 75%; specificity 92%), histologic lipomatosis (area under the curve 0.82, sensitivity 78%; specificity 89%), and intraoperative pancreatic hardness (area under the curve 0.70, sensitivity 78%; specificity 74%). The features of the machine learning-based texture analysis were most accurate in predicting the occurrence of postoperative pancreatic fistula (area under the curve 0.95, sensitivity of 96%; specificity 98%) after pancreatoduodenectomy. This proof-of-principle study suggests the ability of machine learning in recognizing important features of pancreatic texture associated with an increased risk of postoperative pancreatic fistula based on preoperative computed tomography. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs. Summary of Background Data: Steatosis is the hepatic manifestation of the metabolic syndrome, and decreases the liver's ability to handle inflammatory stress or to regenerate after tissue loss. Exercise activates adenosine monophosphate-activated kinase (AMPK) and mitigates steatosis; however, its impact on ischemia-reperfusion injury and regeneration is unknown. Methods: We used a mouse model of simple, diet-induced steatosis and assessed the impact of exercise on metabolic parameters, ischemia-reperfusion injury and regeneration after hepatectomy. The same parameters were evaluated after treatment of mice with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Mice on a control diet served as age-matched controls. Results: A 4-week-exercising program reversed steatosis, lowered insulin levels, and improved glucose tolerance. Exercise markedly enhanced the ischemic tolerance and the regenerative capacity of fatty liver. Replacing exercise with AICAR was sufficient to replicate the above benefits. Both exercise and AICAR improved survival after extended hepatectomy in mice challenged with a Western diet, indicating protection from resection-induced liver failure. Conclusions: Exercise efficiently counteracts the metabolic, ischemic, and regenerative deficits of fatty liver. AICAR acts as an exercise mimetic in settings of fatty liver disease, an important finding given the compliance issues associated with exercise. Exercising, or its substitution through AICAR, may provide a feasible strategy to negate the hepatic consequences of energy-rich diet, and has the potential to extend the application of liver surgery if confirmed in humans. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to use the concept of benchmarking to establish robust and standardized outcome references after the procedure ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy). Background and Aims: The recently developed ALPPS procedure, aiming at removing primarily unresectable liver tumors, has been criticized for safety issues with high variations in the reported morbidity/mortality rates depending on patient, disease, technical characteristics, and center experience. No reference values for relevant outcome parameters are available. Methods: Among 1036 patients registered in the international ALPPS registry, 120 (12%) were benchmark cases fulfilling 4 criteria: patients ≤67 years of age, with colorectal metastases, without simultaneous abdominal procedures, and centers having performed ≥30 cases. Benchmark values, defined as the 75th percentile of the median outcome parameters of the centers, were established for 10 clinically relevant domains. Results: The benchmark values were completion of stage 2: ≥96%, postoperative liver failure (ISGLS-criteria) after stage 2: ≤5%, ICU stay after ALPPS stages 1 and 2: ≤1 and ≤2 days, respectively, interstage interval: ≤16 days, hospital stay after ALPPS stage 2: ≤10 days, rates of overall morbidity in combining both stage 1 and 2: ≤65% and for major complications (grade ≥3a): ≤38%, 90-day comprehensive complication index was ≤22, the 30-, 90-day, and 6-month mortality was ≤4%, ≤5%, and 6%, respectively, the overall 1-year, recurrence-free, liver-tumor-free, and extrahepatic disease-free survival was ≥86%, ≥50%, ≥57%, and ≥65%, respectively. Conclusions: This benchmark analysis sets key reference values for ALPPS, indicating similar outcome as other types of major hepatectomies. Benchmark cutoffs offer valid tools not only for comparisons with other procedures, but also to assess higher risk groups of patients or different indications than colorectal metastases. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To investigate the impact of remote ischemic preconditioning (RIPC) on liver regeneration after major hepatectomy. Summary Background Data: RIPC is a strategy applied at remote sites to mitigate ischemic injury. Unlike other preconditioning approaches, RIPC spares target organs as it acts via systemic VEGF elevations. In the liver, however, VEGF is an important driver of regeneration following resection. Therefore, RIPC may have pro-regenerative effects. Methods: RIPC was applied to C57BL/6 mice through intermittent clamping of the femoral vessels prior to standard 68%-hepatectomy or extended 86%-hepatectomy, with the latter causing liver failure and impaired survival. Liver regeneration was assessed through weight gain, proliferative markers (Ki67, pH3, mitoses), cell cycle-associated molecules, and survival. The role of the VEGF-ID1-WNT2 signaling axis was assessed through WIF1 (a WNT antagonist) and recombinant WNT2 injected prior to hepatectomy. Results: RIPC did not affect regeneration after 68%-hepatectomy, but improved liver weight gain and hepatocyte mitoses after 86%-hepatectomy. Importantly, RIPC raised survival from 40% to 80% after 86%-hepatectomy, indicating the promotion of functional recovery. Mechanistically, the RIPC-induced elevations in VEGF were accompanied by increases in the endothelial transcription factor Id1, its target WNT2, and its hepatocellular effector β-catenin. WIF1 injection prior to 86%-hepatectomy abrogated the RIPC benefits, while recombinant WNT2 had pro-regenerative effects akin to RIPC. Conclusion: RIPC improves the regenerative capacity of marginal liver remnants in a VEGF-dependent way. If confirmed in patients, RIPC may become the preconditioning strategy of choice in the setting of extended liver resections. [ABSTRACT FROM AUTHOR]

Background Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans. Methods The effect of associating liver partition and portal vein ligation for staged hepatectomy and 90% portal vein ligation on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging, histology, and survival experiments. The effects of associating liver partition and portal vein ligation for staged hepatectomy, portal vein ligation, and control sera on cultures of several colorectal cancer cell lines (MC38 and CT26) were tested in vitro. Additionally, the international associating liver partition and portal vein ligation for staged hepatectomy registry enabled us to identify patients with remaining tumor in the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy stage 1. Results Two and 3 weeks after associating liver partition and portal vein ligation for staged hepatectomy stage 1, portal vein ligation, or sham surgery, liver magnetic resonance images showed similar numbers ( P   =   . 14/0.82), sizes ( P   =   . 45/0.98), and growth kinetics ( P   =   . 58/0.68) of intrahepatic tumor. Tumor growth was not different between the associating liver partition and portal vein ligation for staged hepatectomy and portal vein ligation groups after completion of stage 2. Median survival after tumor cell injection was similar after sham surgery (36 days; 95% confidence interval; 27–57 days), completion of associating liver partition and portal vein ligation for staged hepatectomy (42 days; 95% confidence interval; 35–49 days), and portal vein ligation (39 days; 95% confidence interval; 34–43 days, P   =   . 237). Progression of pulmonary metastases and in vitro cell proliferation were comparable among groups. Observations in humans failed to identify any accelerated tumor growth in the future liver remnant within the regenerative phase after associating liver partition and portal vein ligation for staged hepatectomy stage 1. Conclusion The accelerated regeneration process associated with associating liver partition and portal vein ligation for staged hepatectomy does not appear to enhance growth of colorectal metastases. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the effect of Ω3 fatty acids (Ω3FA) on fatty and lean liver in hepatic surgery. Background: The global spread of energy-dense diets has led to an endemic rise in fatty liver disease and obesity. Besides metabolic pathologies, steatosis enhances hepatic sensitivity to ischemia reperfusion (I/R) and impedes liver regeneration (LR). Steatosis limits the application of liver surgery, still the main curative option for liver cancer. Ω3FA are known to reverse steatosis, but how these lipids affect key factors defining surgical outcomes--that is, I/R, LR, and liver malignancy--is less clear. Methods: We established a standardized mouse model of high fat diet (HFD)-induced steatosis followed by V3FA treatment and the subsequent assessment of Ω3FA effects on I/R, LR, and liver malignancy (n = 5/group), the latter through a syngeneic metastasis approach. Fatty liver outcomes were com- pared with lean liver to assess steatosis-independent effects. Nonparametric statistics were applied. Results: Ω3FA reversed HFD-induced steatosis and markedly protected against I/R, improved LR, and prolonged survival of tumor-laden mice. Remarkably, these beneficial effects were also observed in lean liver, albeit at a smaller scale. Notably, mice with metastases in fatty versus lean livers were associated with improved survival. Conclusions: Ω3FA revealed multiple beneficial effects in fatty and lean livers in mice. The improvements in I/R injury, regenerative capacity, and oncological outcomes await confirmatory studies in humans. [ABSTRACT FROM AUTHOR]

Background ALPPS induces rapid liver hypertrophy after stage-1 operation, enabling safe, extended resections (stage-2) after a short period. Recent studies have suggested that partial transection at stage-1 might be associated with a better safety profile. The aim of this study was to assess the amount of liver parenchyma that needs to be divided to achieve sufficient liver hypertrophy in ALPPS. Methods In a bi-institutional, prospective cohort study, nonfibrotic patients who underwent ALPPS with complete ( n = 22) or partial ( n = 23) transection for colorectal liver metastases were analyzed and compared with an external ALPPS cohort ( n = 23). A radiologic tool was developed to quantify the amount of parenchymal transection. Liver hypertrophy and clinical outcome were compared between both techniques. The relationship of partial transection and hypertrophy was investigated further in an experimental murine model of partial ALPPS. Result The median amount of parenchymal transection in partial ALPPS was 61% (range, 34–86%). The radiologic method correlated poorly with the intraoperative surgeon's estimation (r S = 0.258). Liver hypertrophy was equivalent for the partial ALPPS, ALPPS, and external ALPPS cohort (64% vs 60% vs. 64%). Experimental data demonstrated that partial transection of at least 50% induced comparable hypertrophy (137% vs 156%) and hepatocyte proliferation compared to complete transection. Conclusion The study provides clinical and experimental evidence that partial liver partition of at least 50% seems to be equally effective in triggering volume hypertrophy as observed with complete transection and can be re recommended as less invasive alternative to ALPPS. [ABSTRACT FROM AUTHOR]

To develop and validate a simple score to predict postoperative complications by severity after liver resection, using readily available preoperative risk factors.Although liver surgery has enjoyed major development with dramatic reduction in mortality rates, the incidence of serious yet nonlethal complications remains high. No scoring system is currently available to identify those patients at higher risk for a complicated course.Complications were prospectively assessed in 615 consecutive noncirrhotic patients undergoing liver resection at the same institution. In randomly selected 60% of the population, multivariate-logistic-regression analysis was used to develop a score to predict severe complications defined as complications grades III, IV, and mortality (grade V) (Clavien-Dindo classification). The score was validated by calibration within the remaining 40% of the patients.Grades III to V complications occurred in 159 (26%) of the 615 patients after liver resection, 90 (15%) were grade III, 48 (8%) grade IV, and 21 (3%) grade V. Four preoperative parameters were identified as independent predictors including American Society of Anesthesiologists category, transaminases levels (aspartate aminotransferase), extent of liver resection (>3 vs <3 segments), and the need for an additional hepaticojejunostomy or colon resection. A prediction score was calculated on the basis of 60% of the population (369 patients) using the 4 independent predictors ranging from 0 to 10 points. The risk to develop serious postoperative complications was 16% in “low risk” patients (0-2 points), 37% in “intermediate risk” patients (3-5 points) and 60% in “high risk” patients (6-10 points). The predicted mean for absolute risk for grades III to V complications was 27% in the validation population including 40% of the patients (n = 246), whereas the observed risk was 24%. Predicted and observed risks were similar throughout the different risk categories (P = 0.8). The score was significantly associated with hospital and intensive care unit stays. Costs of the entire procedure doubled among the 3 risk groups.This novel and simple score accurately predicts postoperative complications and cost in patients undergoing liver resection. This score allows early identification of patients at risk and may impact not only decision making for surgical intervention but also quality assessment and reimbursement. [ABSTRACT FROM AUTHOR]

Median arcuate ligament syndrome (MALS) involves coeliac artery compression, causing a range of symptoms from chronic pain to life-threatening complications. This case features a 52-year-old patient with recurrent retroperitoneal bleeding from MALS-related inferior pancreaticoduodenal artery aneurysms (PDAAs). Emergency interventions, including surgical bleeding control, angioplasty, percutaneous drainage, and median arcuate ligament release, were conducted. The case highlights challenges in diagnosing and managing MALS-related PDAA, emphasizing the importance of early identification and tailored interventions based on clinical symptoms and imaging. Surgical intervention to release the ligament is the primary treatment, with considerations for prophylactic intervention in PDAA cases. Lack of established PDAA management protocols underscores the need for prompt intervention to prevent complications. In conclusion, this report stresses the association between MALS and PDAA, advocating for early identification and tailored management to mitigate complications., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Both cecal volvolus and Winslow hernia are rare clinical presentations accounting for 1-1.5 and 0.08% of bowel obstructions. The combination of the two phenomena has been described so far in 13 case reports. Our patient underwent laparotomy with lesser Sac opening, manual hernia reduction, right hemicolectomy and partial Foramen closure with two simple stitches of PDS 4.0. Due to the scarcity of literature guidelines are not available, the intraoperative state of the tissues and the likelihood of a hernia recurrence play a decisive role in surgical management., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background and Aims: Alterations in liver histology influence the liver's capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate., Methods: This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis., Results: In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =-0.1 and r =-0.08, respectively), and future liver remnant ( r =-0.15 and r =-0.06, respectively)., Conclusions: ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The presence of diffuse biliary stricturing in Primary Sclerosing Cholangitis (PSC) makes the diagnosis of early Cholangiocarcinoma (CCA) in this context difficult. A finding of incidental CCA on liver explant is associated with poor oncological outcomes, despite this; there remains no international consensus on how best to outrule CCA in this group ahead of transplantation. The objectives of this study were to report the Irish incidence of incidental CCA in individuals with PSC undergoing liver transplantation, and to critically evaluate the accuracy of diagnostic modalities in outruling CCA in our wait-listed PSC cohort., Methods: We conducted a retrospective analysis of our prospectively maintained database, which included all PSC patients wait-listed for liver transplant in Ireland., Results: 4.41% of patients (n = 3) were found to have an incidental finding of CCA on liver explant. Despite only being performed in 35.06% of wait-listed PSC patients (n = 27), Endoscopic Retrograde Cholangiopancreatogram (ERCP) with brush cytology was found to be the most effective tool in correctly outruling CCA in this context; associated with a specificity of 96.15%., Conclusion: Our findings support a future role for routine surveillance of PSC patients awaiting liver transplantation; however further research is required in order to identify which investigative modalities are of optimal diagnostic utility in this specific context., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2022 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Background: The surgical management of bile duct injuries (BDIs) after laparoscopic cholecystectomy (LC) is challenging and the optimal timing of surgery remains unclear. The primary aim of this study was to systematically evaluate the evidence behind the timing of BDI repair after LC in the literature., Aim: To assess timing of surgical repair of BDI and postoperative complications., Methods: The MEDLINE, EMBASE, and The Cochrane Library databases were systematically screened up to August 2021. Risk of bias was assessed via the Newcastle Ottawa scale. The primary outcomes of this review included the timing of BDI repair and postoperative complications., Results: A total of 439 abstracts were screened, and 24 studies were included with 15609 patients included in this review. Of the 5229 BDIs reported, 4934 (94%) were classified as major injury. Timing of bile duct repair was immediate (14%, n = 705), early (28%, n = 1367), delayed (28%, n = 1367), or late (26%, n = 1286). Standardization of definition for timing of repair was remarkably poor among studies. Definitions for immediate repair ranged from < 24 h to 6 wk after LC while early repair ranged from < 24 h to 12 wk. Likewise, delayed (> 24 h to > 12 wk after LC) and late repair (> 6 wk after LC) showed a broad overlap., Conclusion: The lack of standardization among studies precludes any conclusive recommendation on optimal timing of BDI repair after LC. This finding indicates an urgent need for a standardized reporting system of BDI repair., Competing Interests: Conflict-of-interest statement: All the authors declare no conflict of interest for this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Hepatectomy is the only potentially curative treatment of hepatic tumors, but remains challenging in case of multiple, bilobar lesions and those located in the vicinity of the hepatic hilum and hepatic veins. Regenerative liver surgery utilizes the unique ability of the liver to re-grow after tissue loss and vascular deprivation. All concepts subsumed under this term aim to increase the resectability of hepatic tumors by stimulating growth of future liver remnant. Many of these techniques have evolved over the last decades. ALPPS (associated liver partition and portal vein ligation for staged hepatectomy) is an advanced technique combining portal vein ligation and parenchymal transection which gave rise to many variants, all with the common goal of extending resectability. This article reviews techniques currently available for regenerative liver surgery focusing on ALPPS, its mechanisms of liver regeneration, indications, advantages, drawbacks, results and future perspectives., (Celsius.)

Objectives: To evaluate whether a magnetic resonance imaging (MRI) radiomics-based machine learning classifier can predict postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) and to compare its performance to T1 signal intensity ratio (T1 SIratio)., Methods: Sixty-two patients who underwent 3 T MRI before PD between 2008 and 2018 were retrospectively analyzed. POPF was graded and split into clinically relevant POPF (CR-POPF) vs. biochemical leak or no POPF. On T1- and T2-weighted images, 2 regions of interest were placed in the pancreatic corpus and cauda. 173 radiomics features were extracted using pyRadiomics. Additionally, the pancreas-to-muscle T1 SIratio was measured. The dataset was augmented and split into training (70 %) and test sets (30 %). A Boruta algorithm was used for feature reduction. For prediction of CR-POPF models were built using a gradient-boosted tree (GBT) and logistic regression from the radiomics features, T1 SIratio and a combination of the two. Diagnostic accuracy of the models was compared using areas under the receiver operating characteristics curve (AUCs)., Results: Five most important radiomics features were identified for prediction of CR-POPF. A GBT using these features achieved an AUC of 0.82 (95 % Confidence Interval [CI]: 0.74 - 0.89) when applied on the original (non-augmented) dataset. Using T1 SIratio, a GBT model resulted in an AUC of 0.75 (CI: 0.63 - 0.84) and a logistic regression model delivered an AUC of 0.75 (CI: 0.63 - 0.84). A GBT model combining radiomics features and T1 SIratio resulted in an AUC of 0.90 (CI 0.84 - 0.95)., Conclusion: MRI-radiomics with routine sequences provides promising prediction of CR-POPF., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS., Background: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking., Methods: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis., Results: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001)., Conclusions: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

Background: Surgery is the most effective treatment option for neuroendocrine liver metastases (NELM). This study investigated the role of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a novel strategy in treatment of NELM., Methods: The International ALPPS Registry was reviewed to study patients who underwent ALPPS for NELM., Results: From 2010 to 2017, 954 ALPPS procedures from 135 international centers were recorded in the International ALPPS Registry. Of them, 24 (2.5%) were performed for NELM. Twenty-one patients entered the final analysis. Overall grade ≥3b morbidity was 9% after stage 1 and 27% after stage 2. Ninety-day mortality was 5%. R0 resection was achieved in 19 cases (90%) at stage 2. Median follow-up was 28 (19-48) months. Median disease free survival (DFS) was 17.3 (95% CI: 7.1-27.4) months, 1-year and 2-year DFS was 73.2% and 41.8%, respectively. Median overall survival (OS) was not reached. One-year and 2-year OS was 95.2% and 95.2%, respectively., Conclusions: ALPPS appears to be a suitable strategy for inclusion in the multimodal armamentarium of well-selected patients with neuroendocrine liver metastases. In light of the morbidity in this initial series and a high rate of disease-recurrence, the procedure should be taken with caution., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: In a variety of animal models, omega-3 polyunsaturated fatty acids (Ω3-FAs) conferred strong protective effects, alleviating hepatic ischemia/reperfusion injury and steatosis, as well as enhancing regeneration after major tissue loss. Given these benefits along with its safety profile, we hypothesized that perioperative administration of Ω3-FAs in patients undergoing liver surgery may ameliorate the postoperative course. The aim of this study was to investigate the perioperative use of Ω3-FAs to reduce postoperative complications after liver surgery., Methods: Between July 2013 and July 2018, we carried out a multicentric, double-blind, randomized, placebo-controlled trial designed to test whether 2 single intravenous infusions of Omegaven® (Ω3-FAs) vs. placebo may decrease morbidity. The primary endpoints were postoperative complications by severity (Clavien-Dindo classification) integrated within the comprehensive complication index (CCI)., Results: A total of 261 patients (132 in the Omegaven and 129 in the placebo groups) from 3 centers were included in the trial. Most cases (87%, n = 227) underwent open liver surgery and 56% (n = 105) were major resections (≥3 segments). In an intention-to-treat analysis including the dropout cases, the mortality rate was 4% and 2% in the Omegaven and placebo groups (odds ratio0.40;95% CI 0.04-2.51; p = 0.447), respectively. Any complications and major complications (Clavien-Dindo ≥ 3b) occurred in 46% vs. 43% (p = 0.709) and 12% vs. 10% (p = 0.69) in the Omegaven and placebo groups, respectively. The mean CCI was 17 (±23) vs.14 (±20) (p = 0.417). An analysis excluding the dropouts provided similar results., Conclusions: The routine perioperative use of 2 single doses of intravenous Ω3-FAs (100 ml Omegaven) cannot be recommended in patients undergoing liver surgery (Grade A recommendation)., Lay Summary: Despite strong evidence of omega-3 fatty acids having liver-directed, anti-inflammatory and pro-regenerative action in various rodent models, 2 single omega-3 fatty acid infusions given to patients before and during liver surgery failed to reduce complications. Because single omega-3 fatty acid infusions failed to confer liver protection in this trial, they cannot currently be recommended., Trial Registration: ClinicalTrial.gov: ID: NCT01884948; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215., (Copyright © 2019. Published by Elsevier B.V.)

Background: Based on the International ALPPS registry, we have recently proposed two easily applicable risk models (pre-stage1 and 2) for predicting 90-day mortality in ALPPS but a validation of both models has not been performed yet., Methods: The validation cohort (VC) was composed of subsequent cases of the ALPPS registry and cases of centers outside the ALPPS registry., Results: The VC was composed of a total of 258 patients including 70 patients outside the ALPPS registry with 32 cases of early mortalities (12%). Development cohort (DC) and VC were comparable in terms of patient and surgery characteristics. The VC validated both models with an acceptable prediction for the pre-stage 1 (c-statistic 0.64, P = 0.009 vs. 0.77, P < 0.001) and a good prediction for the pre-stage 2 model (c-statistic 0.77, P < 0.001 vs. 0.85, P < 0.001) as compared to the DC. Overall model performance measured by Brier score was comparable between VC and DC for the pre-stage 1 (0.089 vs. 0.081) and pre-stage 2 model (0.079 vs. 0087)., Conclusion: The ALPPS risk score is a fully validated model to estimate the individual risk of patients undergoing ALPPS and to assist clinical decision making to avoid procedure-related early mortality after ALPPS., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo-YAP1 pathway, a key controller of organ size. Yes-associated protein 1 (YAP1)-a growth effector usually restrained by Hippo signaling-is believed to be of particular importance; however, its role in liver regeneration remains ill-defined. To explore its function, we knocked down YAP1 prior to standard 70%-hepatectomy (sHx) using a hepatocyte-specific nanoformulation. Knockdown was effective during the major parenchymal growth phase (S-phase/M-phase peaks at 32 hours/48 hours post-sHx). Liver weight gain was completely suppressed by the knockdown at 32 hours, but was reaccelerated toward 48 hours. Likewise, proliferative markers, Ccna2/b2 and YAP1 target gene expression were downregulated at 32 hours, but re-elevated at 48 hours post-sHx. Nonetheless, knockdown slightly compromised survival after sHx. When assessing a model of resection-induced liver failure (extended 86%-hepatectomy, eHx) featuring deficient S- and M-phase progression, YAP1 was not induced at 32 hours, but upregulated at 48 hours post-eHx, confirming its dissociation from M-phase regulation. Therefore, YAP1 is vital to push hepatocytes into cycle and through the S-phase, but is not required for further cell cycle progression during liver regeneration. The examination of YAP1 in human livers suggested its function is conserved in the regenerating mammalian liver.

Background: In 2016, the International Study Group of Pancreatic Fistula (ISGPS) proposed an updated definition for postoperative pancreatic fistula (POPF). Pancreas texture (PT) is an established risk factor of POPF. The definition of soft vs. hard texture, however, remains elusive., Methods: A systematic search was performed to identify PT definitions and a meta-analysis linking POPF to PT using the updated ISGPS definition., Results: 122 studies including 22 376 patients were identified. Definition criteria for PT varied among studies and most classified PT in hard and soft based on intraoperative subjective assessment. The total POPF rate (pooled grades B and C) after pancreatoduodenectomy was 14.5% (n = 10 395) and 15.5% (n = 3767) after distal pancreatectomy. In pancreatoduodenectomy, POPF rate was higher in soft compared to hard pancreas (RR, 4.4, 3.3 to 6.1; p < 0.001; n = 6393), where PT grouped as soft and hard. No data were available for intermediate PT., Conclusion: The reported POPF rates may be used in planning future prospective studies. A widely accepted definition of PT is lacking and a correlation with the risk of POPF is based on subjective evaluation, which is still acceptable. Classification of PT into 2-groups is more reasonable than classification into 3-groups., (Copyright © 2018. Published by Elsevier Ltd.)

Interaction between sinusoidal endothelial cells and hepatocytes is a prerequisite for liver function. Upon tissue loss, both liver cell populations need to be regenerated. Repopulation occurs in a coordinated pattern, first through the regeneration of parenchyme (hepatocytes), which then produces vascular endothelial growth factor (VEGF) to enable the subsequent angiogenic phase. The signals that instruct hepatocytes to induce timely VEGF remain unidentified. Given that liver is highly vascularized, we reasoned that fluctuations in oxygenation after tissue loss may contribute to the coordination between hepatocyte and sinusoidal endothelial cell proliferation. To prevent drops in oxygen after hepatectomy, mice were pretreated with inositol trispyrophosphate (ITPP), an allosteric effector of hemoglobin causing increased O 2 release from heme under hypoxic conditions. ITPP treatment delayed liver weight gain after hepatectomy. Comparison with controls revealed the presence of a hypoxic period around the peak of hepatocyte mitosis. Inhibition of hypoxia led to deficient hepatocyte mitosis, suppressed the regenerative Vegf wave, and abrogated the subsequent reconstruction of the sinusoidal network. These ITPP effects were ongoing with the reduction in hepatocellular hypoxia inducible factor 2a (Hif2a). In contrast, Hif1a was unaffected by ITPP. Hif2a knockdown phenocopied all effects of ITPP, including the mitotic deficiencies, Vegf suppression, and angiogenic failure., Conclusions: Oxygen is a key regulator of liver regeneration. Hypoxia-inherent to the expansion of parenchyme-activates Hif2a to couple hepatocyte mitosis with the angiogenic phase. Hif2a acts as a safeguard to initiate sinusoidal reconstruction only upon successful hepatocyte mitosis, thereby enforcing a timely order onto cell type-specific regeneration patterns. These findings portray the hypoxia-driven Hif2a-Vegf axis as a prime node in coordinating sinusoidal endothelial cell-hepatocyte crosstalk during liver regeneration. (Hepatology 2016;64:2198-2209)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background: Irreversible electroporation is increasingly used for treatment of solid tumors, but safety data remain scarce. This study aimed to describe intraoperative adverse events associated with irreversible electroporation in patients undergoing solid tumor ablation., Methods: We analyzed demographic and intraoperative data for patients (n = 43) undergoing irreversible electroporation for hepato-pancreato-biliary and retroperitoneal malignancies (2012 to 2015). Adverse events were defined as cardiac, surgical, or equipment-related., Results: Adverse events (n = 20, 47%) were primarily cardiac (90%, n = 18), including blood pressure elevation (77%, n = 14/18) and arrhythmia (16%, n = 7/43). All but one was managed medically, 1 patient with arrhythmia required termination of ablation. Bleeding and technical problems with the equipment occurred in 1 patient each. Multivariable analysis revealed previous cardiovascular disease and needle placement close to the celiac trunk associated with increased likelihood for cardiac events., Conclusions: Intraoperative cardiac adverse events are common during irreversible electroporation but rarely impair completion of the procedure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Posthepatectomy liver failure (PHLF) may occur after ALPPS (Associating liver partition and portal vein ligation for staged hepatectomy) despite a sufficient standardized future liver remnant (sFLR) volume. The aim of this study was to test kinetic growth rate (KGR) after ALPPS stage 1, describing the percentage increase of sFLR per day, as a predictor of PHLF after completion of ALPPS., Methods: The ability of KGR to predict PHLF after ALPPS stage 2 was investigated in 38 patients. PHLF was defined according to the "50-50" and ISGLS criteria., Results: Completion of ALPPS was achieved in 95% (36/38) of patients. The incidence of PHLF was 22% (8/36) and 36% (13/36) according to "50-50" and ISGLS criteria, respectively. Whereas a sFLR cut off at 30% alone failed to predict PHLF, KGR ≥6%/day after stage 1 was associated with a significant reduced risk of PHLF ("50-50", p = 0.03/ISGLS, p = 0.03) after stage 2. Adherence to both concomitant KGR ≥6%/day and sFLR ≥30% reduced the incidence of PHLF to 0%., Conclusions: Assessment of KGR is a novel tool to estimate the risk of PHLF after ALPPS. Respecting KGR and sFLR after ALPPS stage 1 may increase safety in patients undergoing ALPPS., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the use of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI)-derived fat- and liver function-measurements for prediction of future liver remnant (FLR) growth after portal vein occlusion (PVO) in patients scheduled for major liver resection., Methods: Forty-five patients (age, 59 ± 13.9 y) who underwent Gd-EOB-DTPA-enhanced liver MRI within 24 ± 18 days prior to PVO were included in this study. Fat-Signal-Fraction (FSF), relative liver enhancement (RLE) and corrected liver-to-spleen ratio (corrLSR) of the FLR were calculated from in- and out-of-phase (n=42) as well as from unenhanced T1-weighted, and hepatocyte-phase images (n=35), respectively. Kinetic growth rate (KGR, volume increase/week) of the FLR after PVO was the primary endpoint. Receiver operating characteristics analysis was used to determine cutoff values for prediction of impaired FLR-growth., Results: FSF (%) showed significant inverse correlation with KGR (r=-0.41, p=0.008), whereas no significant correlation was found with RLE and corrLSR. FSF was significantly higher in patients with impaired FLR-growth than in those with normal growth (%FSF, 8.1 ± 9.3 vs. 3.0 ± 5.9, p=0.02). ROC-analysis revealed a cutoff-FSF of 4.9% for identification of patients with impaired FLR-growth with a specificity of 82% and sensitivity of 47% (AUC 0.71 [95%CI:0.54-0.87]). Patients with impaired FLR-growth according to the FSF-cutoff showed a tendency towards higher postoperative complication rates (posthepatectomy liver failure in 50% vs. 19%)., Conclusions: Liver fat-content, but not liver function derived from Gd-EOB-DTPA-enhanced MRI is a predictor of FLR-growth after PVO. Thus, liver MRI could help in identifying patients at risk for insufficient FLR-growth, who may need re-evaluation of the therapeutic strategy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

With the advent of novel and somewhat effective chemotherapy against pancreas cancer, several groups developed a new interest on locally advanced pancreatic cancer (LAPC). Unresectable tumors constitute up to 80% of pancreatic cancer (PC) at the time of diagnosis and are associated with a 5-year overall survival of less than 5%. To control those tumors locally, with perhaps improved patients survival, significant advances were made over the last 2 decades in the development of ablation methods including cryoablation, radiofrequency ablation, microwave ablation, high intensity focused ultrasound and irreversible electroporation (IRE). Many suggested a call for caution for possible severe or lethal complications in using such techniques on the pancreas. Most fears were on the heating or freezing of the pancreas, while non-thermal ablation (IRE) could offer safer approaches. The multimodal therapies along with high-resolution imaging guidance have created some enthusiasm toward ablation for LAPC. The impact of ablation techniques on primarily non-resectable PC remains, however, unclear., (© 2016 S. Karger AG, Basel.)

Background: Perihilar cholangiocarcinoma is usually unresectable at the time of diagnosis. Only few patients are candidates for a potential curative treatment. For those patients, prognosis is strongly related to negative resection margin and lymph node status. Thus, a certain benchmark of lymph node count is necessary to secure relevant lymph node recovery and to avoid understaging. However, the required minimum number of retrieved lymph nodes remains unclear for perihilar cholangiocarcinoma. The 7th American Joint Committee on Cancer tumor, nodes, metastases edition increased the requirement for the histologic examination of lymph nodes in perihilar cholangiocarcinoma patients from 3 to 15. The applicability of such recommendation appears difficult and questionable. Therefore, the purpose of this systematic review is to evaluate the number of retrieved lymph nodes for staging of patients undergoing surgery for perihilar cholangiocarcinoma., Methods: The MEDLINE, EMBASE, and The Cochrane Library databases were systematically screened up to December 2014. All studies reporting the number of lymph node count in perihilar cholangiocarcinoma were included and assessed for eligibility., Results: A total of 725 abstracts were screened and 20 studies were included for analysis, comprising almost 4,000 patients. The cumulative median lymph node count was 7 (2 to 24). A median lymph node count greater than or equal to 15 was reported in 9% of perihilar cholangiocarcinoma patients and could only be achieved in extended lymphadenectomy. Subgroup analysis revealed a median lymph node count of 7 (range 7 to 9), which was associated with the detection of most lymph node positive patients and showed the lowest risk for understaging patients. Lymph node count greater than or equal to 15 did not increase detection rate of lymph node positive patients., Conclusions: This systematic analysis suggests that lymph node count greater than or equal to 7 is adequate for prognostic staging, while lymph node count greater than or equal to 15 does not improve detection of patients with positive lymph nodes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Epidural analgesia (EDA) is a common analgesia regimen in liver resection, and is accompanied by sympathicolysis, peripheral vasodilatation and hypotension in the context of deliberate intraoperative low central venous pressure. This associated fall in mean arterial pressure may compromise renal blood pressure autoregulation and lead to acute kidney injury (AKI). This study investigated whether EDA is a risk factor for postoperative AKI after liver surgery., Methods: The incidence of AKI was investigated retrospectively in patients who underwent liver resection with or without EDA between 2002 and 2012. Univariable and multivariable analyses were performed including recognized preoperative and intraoperative predictors of posthepatectomy renal failure., Results: A series of 1153 patients was investigated. AKI occurred in 8·2 per cent of patients and was associated with increased morbidity (71 versus 47·3 per cent; P = 0·003) and mortality (21 versus 0·3 per cent; P <  0·001) rates. The incidence of AKI was significantly higher in the EDA group (10·1 versus 3·7 per cent; P = 0·003). Although there was no significant difference in the incidence of AKI between patients undergoing minor hepatectomy with or without EDA (5·2 versus 2·7 per cent; P = 0·421), a substantial difference in AKI rates occurred in patients undergoing major hepatectomy (13·8 versus 5·0 per cent; P = 0·025). In multivariable analysis, EDA remained an independent risk factor for AKI after hepatectomy (P = 0·040)., Conclusion: EDA may be a risk factor for postoperative AKI after major hepatectomy., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Cholangiocarcinoma is a lethal disease with increasing incidence worldwide. Perihilar cholangiocarcinoma represents the most common type of cholangiocarcinoma. Despite major development on surgical strategies over the past 20 years, the 5-year survival rate after surgery has remained below 40%, often in the vicinity of 20%. Most perihilar cholangiocarcinomas, however, are unresectable at the time of the diagnosis. The recent use of aggressive approaches based on better image modality, specific perioperative management, and a multidisciplinary approach have enabled to convert the use of palliative therapies to more radical surgery. This review focuses on the recent advances in surgical treatment for perihilar cholangiocarcinoma including liver transplantation with their respective impact on patient survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose of Review: The purpose of this review is to evaluate the most current strategies of surgical treatment for cholangiocarcinoma including liver resection and transplantation., Recent Findings: More aggressive surgical approaches have emerged over the past decade to treat patients previously considered to have unresectable lesions, which include combined hepatectomy with vascular resection, liver mass manipulation, oncological nontouch technique and liver transplantation., Summary: Cholangiocarcinoma can occur anywhere along the biliary system. Its detection rate, and consequently its incidence, has risen possibly because of improvements in diagnostic imaging. Cholangiocarcinomas are presently understood within three distinct categories: intrahepatic, perihilar and distal tumors. The perihilar type is the most common, followed by the distal and intrahepatic types. This division has therapeutic relevance because the type of surgery depends on the anatomical location and extension of the tumor. This review will primarily focus on those circumstances in which a hepatectomy is required, which provides the greatest chance of cure. In this setting, liver transplantation for perihilar cholangiocarcinoma has resurged as an excellent option for a selective group of patients, when associated with a neoadjuvant chemoradiation protocol. Despite more aggressive surgical approaches, many cases remain unresectable with a poor prognosis.

Background: Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics., Methods: Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman's rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts., Results: Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p=0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts., Conclusions: Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.

A 34-year-old patient was scheduled for valve replacement to treat a symptomatic mitral regurgitation. The preoperative work-up incidentally discovered an intra-abdominal cystic tumour extending from the epigastrium to the pelvic region on a computed tomography scan. The patient had no abdominal symptoms by the giant cyst from unkown origin. An open "en bloc" resection disclosed a large cyst in the mesocolon. Pathological examination, including immunohistochemistry, enabled the diagnosis of a mesenteric cystic lymphangioma. Long-term follow-up of 12 months shows no recurrence. Mesenteric cystic lymphangioma, which is extremely rare in adults, is a challenge to diagnose and needs complete resection to ensure dignity and to avoid recurrence., (© JSCR.)

Background: Extracellular matrix metalloprotease inducer (EMMPRIN) induces matrix metalloproteinase (MMP) expression, tumor-stroma cell interaction, and invasion/angiogenesis. The objectives of the current study were to find the first evidence of a prognostic impact of total and relative EMMPRIN expression in colorectal cancer cells and to analyze EMMPRIN in bone marrow-disseminated tumor cells and normal cells from 2 different gastrointestinal cancer entities., Methods: Tumors and normal tissues from 40 patients with colorectal cancer who were followed prospectively (median follow-up, 31 months) were analyzed for EMMPRIN by immunohistochemistry. Bone marrow from 51 patients (13 patients with gastric cancer and 38 patients with colorectal cancer) with evidence of disseminated tumor cells was screened for EMMPRIN in tumor cells and normal cells (cytokeratin 18/EMMPRIN double immunocytochemistry)., Results: A significant correlation between poor disease-specific survival (P=.037; Kaplan-Meier method; Mantel-Cox log-rank tests) and an increased ratio of EMMPRIN in tumor cells versus corresponding normal epithelial cells were observed. Furthermore, the relative increase of EMMPRIN was associated with a trend toward poor overall and recurrence-free survival. High relative EMMPRIN expression was associated significantly with positive metastasis status (M1) (P=.001) and with a trend towards advanced pathologic tumor classification. Sixteen percent of disseminated tumor cells in bone marrow samples from patients with colorectal cancer and 48.5% of disseminated tumor cells in bone marrow samples from patients with gastric cancer stained positive for EMMPRIN, and EMMPRIN on micrometastatic cells was associated significantly with parameters of tumor progression (M status, noncurative resectability). A minority of normal bone marrow cells were stained for EMMPRIN, suggesting their suitability for molecular targeting., Conclusions: To the authors' knowledge, this study was the first to indicate that increased relative EMMPRIN protein in tumor-specific cells compared with normal cells predicts poor disease-specific survival in patients with colorectal cancer and that EMMPRIN in primary and bone marrow-disseminated tumor cells is associated with clinical markers of tumor progression in patients with colorectal/gastric cancer., (Copyright (c) 2009 American Cancer Society.)