Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation.

BACKGROUND: While resection remains the only curative option for perihilar cholangiocarcinoma, it is well known that such surgery is associated with a high risk of morbidity and mortality. Nevertheless, beyond facing life-threatening complications, patients may also develop early disease recurrence, defining a "futile" outcome in perihilar cholangiocarcinoma surgery. The aim of this study is to predict the high-risk category (futile group) where surgical benefits are reversed and alternative treatments may be considered. METHODS: The study cohort included prospectively maintained data from 27 Western tertiary referral centers: the population was divided into a development and a validation cohort. The Framingham Heart Study methodology was used to develop a preoperative scoring system predicting the "futile" outcome. RESULTS: A total of 2271 cases were analyzed: among them, 309 were classified within the "futile group" (13.6%). American Society of Anesthesiology (ASA) score ≥ 3 (OR 1.60; p = 0.005), bilirubin at diagnosis ≥50 mmol/L (OR 1.50; p = 0.025), Ca 19-9 ≥ 100 U/mL (OR 1.73; p = 0.013), preoperative cholangitis (OR 1.75; p = 0.002), portal vein involvement (OR 1.61; p = 0.020), tumor diameter ≥3 cm (OR 1.76; p < 0.001), and left-sided resection (OR 2.00; p < 0.001) were identified as independent predictors of futility. The point system developed, defined three (ie, low, intermediate, and high) risk classes, which showed good accuracy (AUC 0.755) when tested on the validation cohort. CONCLUSIONS: The possibility to accurately estimate, through a point system, the risk of severe postoperative morbidity and early recurrence, could be helpful in defining the best management strategy (surgery vs. nonsurgical treatments) according to preoperative features.

Higher Postoperative Mortality and Inferior Survival After Right-Sided Liver Resection for Perihilar Cholangiocarcinoma: Left-Sided Resection is Preferred When Possible.

BACKGROUND: A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA. METHODS: Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS). RESULTS: Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p < 0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p < 0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p < 0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p < 0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities. CONCLUSIONS: A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred.

Failure to Rescue After Resection of Perhilar Cholangiocarcinoma in an International Multicenter Cohort.

BACKGROUND: Failure to rescue (FTR) is defined as the inability to prevent death after the development of a complication. FTR is a parameter in evaluating multidisciplinary postoperative complication management. The aim of this study was to evaluate FTR rates after major liver resection for perihilar cholangiocarcinoma (pCCA) and analyze factors associated with FTR. PATIENTS AND METHOD: Patients who underwent major liver resection for pCCA at 27 centers were included. FTR was defined as the presence of a Dindo grade III or higher complication followed by death within 90 days after surgery. Liver failure ISGLS grade B/C were scored. Multivariable logistic analysis was performed to identify predictors of FTR and reported using odds ratio and 95% confidence intervals. RESULTS: In the 2186 included patients, major morbidity rate was 49%, 90-day mortality rate 13%, and FTR occurred in 24% of patients with a grade III or higher complication. Across centers, major complication rate varied from 19 to 87%, 90-day mortality rate from 5 to 33%, and FTR ranged from 11 to 50% across hospitals. Age [1.04 (1.02-1.05) years], ASA 3 or 4 [1.40 (1.01-1.95)], jaundice at presentation [1.79 (1.16-2.76)], right-sided resection [1.45 (1.06-1.98)], and annual hospital volume < 6 [1.44 (1.07-1.94)] were positively associated with FTR. When liver failure is included, the odds ratio for FTR is 9.58 (6.76-13.68). CONCLUSION: FTR occurred in 24% of patients after resection for pCCA. Liver failure was associated with a nine-fold increase of FTR and hospital volume below six was also associated with an increased risk of FTR.

Preoperative endoscopic biliary drainage by metal versus plastic stents for resectable perihilar cholangiocarcinoma.

BACKGROUND AND AIMS: Adequate preoperative biliary drainage (PBD) is recommended in most patients with resectable perihilar cholangiocarcinoma (pCCA). Most expert centers use endoscopic plastic stents rather than self-expandable metal stents (SEMSs). In the palliative setting, however, use of SEMSs has shown longer patency and superior survival. The aim of this retrospective study was to compare stent dysfunction of SEMSs versus plastic stents for PBD in resectable pCCA patients. METHODS: In this multicenter international retrospective cohort study, patients with potentially resectable pCCAs who underwent initial endoscopic PBD from 2010 to 2020 were included. Stent failure was a composite end point of cholangitis or reintervention due to adverse events or insufficient PBD. Other adverse events, surgical outcomes, and survival were recorded. Propensity score matching (PSM) was performed on several baseline characteristics. RESULTS: A total of 474 patients had successful stent placement, of whom 61 received SEMSs and 413 plastic stents. PSM (1:1) resulted in 2 groups of 59 patients each. Stent failure occurred significantly less in the SEMSs group (31% vs 64%; P < .001). Besides less cholangitis after SEMSs placement (15% vs 31%; P = .012), other PBD-related adverse events did not differ. The number of patients undergoing surgical resection was not significantly different (46% vs 49%; P = .71). Complete intraoperative SEMSs removal was successful and without adverse events in all patients. CONCLUSIONS: Stent failure was lower in patients with SEMSs as PBD compared with plastic stents in patients with resectable pCCA. Removal during surgery was quite feasible. Surgical outcomes were similar.

Assessment of antiarthritic potential of Asparagus dumosus using formaldehyde and CFA-induced arthritic models in rats via modulation of oxidative stress biomarkers and mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2.

Medicinal plants play a pivotal role in the prevention of chronic non-communicable diseases including arthritis. Despite the traditional use of Asparagus dumosus in arthritis, it has not been studied yet for its effectiveness in arthritis. This study was aimed to explore the antiarthritic potential of A. dumosus in formaldehyde and complete Freund's adjuvant (CFA)-induced arthritic rats. Body weight, arthritic index, hepatic oxidative stress, hematological, biochemical and inflammatory markers were assessed using ELISA, whilst qRT-PCR studies were carried out for the mRNA expression of IL-1b, IL-6, RANKL, OPG, TNF-α and COX-2 genes. GCMS and HPLC analysis were performed to identify the secondary metabolites of A. dumosus. From day 8 to 28 post-administration of formaldehyde and CFA, oral administration of A. dumosus (600, 300 and 150 mg/kg) showed a noteworthy improvement (p < 0.001) in the body weights, immune organ weights, serum levels of rheumatoid (RA) factor, C-reactive protein, TNF-α and IL-6 levels in arthritic rats similar to the effect of piroxicam and methotrexate. Subsequently, the administration of A. dumosus to formaldehyde and CFA-challenged rats, caused a marked decrease (p < 0.001) in the mRNA expression of IL-1b, IL-6, OPG, RANKL, TNF-α and COX-2 genes in treated rats. Likewise, when assessed for antioxidant potential, A. dumosus produced a pronounced (p < 0.001) reduction in malondialdehyde (MDA) levels and hydrogen peroxide (H2O2) production, whilst a dose-dependent (p < 0.001) increase in catalase (CAT) and superoxide dismutase (SOD) activities was recorded. GCMS profiling of A. dumosus presented benzaldehyde, 3-hydroxy-4-methoxy-, 1-decanol and undecane as plant compositions, whereas HPLC fingerprinting displayed quercetin, benzaldehyde, 3-hydroxy-4-methoxy-, gallic acid and cinnamic acid as plants constituents. These results depict that A. dumosus possesses anti-arthritic effect mediated possibly through attenuation of arthritic indices, chronic inflammatory and oxidative stress biomarkers along with down-regulation in the mRNA expression of arthritic candid genes.

Novel antiarthritic mechanisms of Azelaic acid against CFA-induced arthritis in rats by modulating pro- and anti-inflammatory cytokines network.

An immunologic system attacking the body's own tissues is a hallmark of autoimmune disorders, which encompass a wide range of unique conditions. Numerous essential biologic functions, including the regulation of the immune system, inflammation, cell division, and tissue repair, are carried out by cytokines. Natural compounds are an effective treatment for autoimmune illnesses by modulation of inflammatory cytokines and infiltration of leukocytes into the inflamed tissue. Here, anti-arthritic study was carried out using oral administration of Azelaic acid (AzA) for 28 days with doses (20, 40, and 80 mg/kg) in Complete Freund's Adjuvant (CFA) induced arthritis model. AzA ameliorated the adjuvant-induced arthritis by decreasing arthritic score, paw volume, improved body-weight alterations and serum levels of PGE2, 5-LOX and anti-ccp. AzA showed significant down regulation of NF-κB, COX-II, TNF-α, IL-17, IL-1ß, IL-6, and up regulation of IL4 and IL10. Hemoglobin and RBCs count remarkably increased and ESR, CRP, platelets, WBCs levels markedly reduced in post treatment. In addition, the weakened SOD (superoxide dismutase), Catalase (CAT), Glutathione (GSH) activity and the increased levels of malondialdehyde (MDA) were all reversed by AzA treatment. And showed improved radiographical and histologic alterations in the structure of the joints. Molecular docking studies targeting COX-II, iNOS, TNF-α, 5-LOX, IL4, IL10, IL-6, and IL-17 establish a correlation between theoretical and experimental results. Results showed that AzA inhibit pro-inflammatory cytokines (COX-II, TNF-α, 5-LOX, IL-17, NF-κB, IL-1ß, and IL-6) and increase anti-inflammatory cytokines, which supported the anti-arthritic and immunomodulatory potential of AzA.

Molecular insights of Eucalyptol (1,8-Cineole) as an anti-arthritic agent: in vivo and in silico analysis of IL-17, IL-10, NF-κB, 5-LOX and COX-2.

The monoterpene oxide, Eucalyptol (1,8-Cineole), a primary component of eucalyptus oil, has been evaluated pharmacologically for anti-inflammatory and analgesic activity. Current research aimed to evaluate Eucalyptol's anti-arthritic potential in a Complete Freund's adjuvant induced arthritis that resembles human rheumatoid arthritis. Polyarthritis developed after 0.1 mL CFA injection into the left hind footpad in rats. Oral administration of Eucalyptol at various doses (100, 200 and 400 mg/kg) significantly reduced paw edema, body weight loss, 5-LOX, PGE2 and Anti-CCP levels. Real-time PCR investigation showed significant downregulation of COX-2, TNF-α, NF-κB, IL-17, IL-6, IL-1ß and upregulation of IL-4 and IL-10 in Eucalyptol treated groups. Hemoglobin and RBCs counts significantly increased post-treatment with Eucalyptol while ESR, CRP, WBCs and platelets count significantly decreased. Eucalyptol significantly increased Superoxide Dismutase, Catalase and Glutathione levels compared to CFA-induced arthritic control however, MDA significantly decreased post-treatment. Further, radiographic and histopathological examination of the ankle joints of rodents administered Eucalyptol revealed an improvement in the structure of the joints. Piroxicam was taken as standard. Furthermore, molecular docking findings supported the anti-arthritic efficacy of Eucalyptol exhibited high binding interaction against IL-17, TNF-α, IL-4, IL-10, iNOS NF-κB, 5-LOX, and COX-2. Eucalyptol has reduced the severity of CFA induced arthritis by promoting anti-inflammatory cytokines for example IL-4, IL-10 and by inhibiting pro-inflammatory cytokines such as 5-LOX, COX-2, IL-17, NF-κB, TNF-α, IL-6 and IL-1ß. Therefore, Eucalyptol might be as a potential therapeutic agent because of its pronounced anti-oxidant and anti-arthritic activity.

ß-Citronellol: a potential anti-inflammatory and gastro-protective agent-mechanistic insights into its modulatory effects on COX-II, 5-LOX, eNOS, and ICAM-1 pathways through in vitro, in vivo, in silico, and network pharmacology studies.

BACKGROUND: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of ß- Citronellol using in vitro, in vivo assays and in silico approaches. METHODS: In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of ß-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA). RESULTS: ß-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat's paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, ß-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues. CONCLUSIONS: The anti-inflammatory, anti-oxidant, and gastro-protective effects of ß-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers.

British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma.

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.

Assessment of inter-centre agreement across multidisciplinary team meetings for patients with retroperitoneal sarcoma.

BACKGROUND: Decision-making in the management of patients with retroperitoneal sarcoma is complex and requires input from a number of different specialists. The aim of this study was to evaluate the levels of agreement in terms of resectability, treatment allocation, and organs proposed to be resected across different retroperitoneal sarcoma multidisciplinary team meetings. METHODS: The CT scans and clinical information of 21 anonymized retroperitoneal sarcoma patients were sent to all of the retroperitoneal sarcoma multidisciplinary team meetings in Great Britain, which were asked to give an opinion about resectability, treatment allocation, and organs proposed to be resected. The main outcome was inter-centre reliability, which was quantified using overall agreement, as well as the chance-corrected Krippendorff's alpha statistic. Based on the latter, the level of agreement was classified as: 'slight' (0.00-0.20), 'fair' (0.21-0.40), 'moderate' (0.41-0.60), 'substantial' (0.61-0.80), or 'near-perfect' (>0.80). RESULTS: Twenty-one patients were reviewed at 12 retroperitoneal sarcoma multidisciplinary team meetings, giving a total of 252 assessments for analysis. Consistency between centres was only 'slight' to 'fair', with rates of overall agreement and Krippendorff's alpha statistics of 85.4 per cent (211 of 247) and 0.37 (95 per cent c.i. 0.11 to 0.57) for resectability; 80.4 per cent (201 of 250) and 0.39 (95 per cent c.i. 0.33 to 0.45) for treatment allocation; and 53.0 per cent (131 of 247) and 0.20 (95 per cent c.i. 0.17 to 0.23) for the organs proposed to be resected. Depending on the centre that they had attended, 12 of 21 patients could either have been deemed resectable or unresectable, and 10 of 21 could have received either potentially curative or palliative treatment. CONCLUSIONS: Inter-centre agreement between retroperitoneal sarcoma multidisciplinary team meetings was low. Multidisciplinary team meetings may not provide the same standard of care for patients with retroperitoneal sarcoma across Great Britain.

Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. METHODS: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSION: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. METHODS: A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. RESULTS: Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2- to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. CONCLUSION: These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.

Liver surgery is an effective treatment for liver tumours. Liver failure is a major problem in patients with a poor liver quality or having large operations. The treatment options for liver failure are limited, with high death rates. To estimate patient risk, assessing liver function before surgery is important. Many methods exist for this purpose, including functional, blood, and imaging tests. This guideline summarizes the available literature and expert opinions, and aids clinicians in planning safe liver surgery.

Association between posterior tibial slope and anatomic spinopelvic parameters: a retrospective cross-sectional study.

PURPOSE: Only a few publications considered the influence of the spinopelvic parameters on below-hip anatomy. There is a lack of evidence about the relationship between the anatomic spinopelvic parameters and the posterior tibial slope (PTS). Therefore, the aim of this study was to analyze the association between fixed anatomic spinopelvic parameters and PTS. METHODS: Adult patients presenting with lumbar, thoracic, or cervical complaints together with knee pain at a single hospital between 2017 to 2022 with available standing full-spine lateral radiograph and lateral knee radiograph were retrospectively reviewed. The measured parameters included the pelvic incidence (PI), the sacral kyphosis (SK), the pelvisacral angle, the sacral anatomic orientation (SAO), the sacral table angle, the sacropelvic angle and the PTS. Pearson's correlations and linear regression analyses were conducted. RESULTS: A total of 80 patients (44 women), median age 63 years were analyzed. A strong positive correlation was identified between PI and PTS (r = 0.70, p < 0.001). A strong negative correlation was observed between PI and SAO (r = - 0.74, p < 0.001). A strong positive correlation was observed between PI and SK (r = 0.81, p < 0.001). A univariable linear regression analysis showed that PTS can be deduced from PI according to the following formula: PTS = 0.174 × PI - 1.138. CONCLUSION: This study is the first to support a positive correlation between the PI and the PTS. We demonstrate that knee anatomy is individually correlated to pelvic shape and therefore influences spinal posture.

Role of medicinal herbs and phytochemicals in post burn management.

Burn management is a natural and distinctly programmed process involving overlapping phases of hemostasis, inflammation, proliferation and remodeling. Burn wound healing involves initiation of inflammation, re-epithelialization, granulation, neovascularization and wound contraction. Despite the availability of multiple preparations for management of burn wound, there is dire need for efficacious alternative agents. Current approaches for burn wound management include pharmaceutical agents and antibiotics. However, high cost of synthetic drugs and accelerated resistance to antibiotics is challenging for both developed and developing nations. Among alternative options, medicinal plants have been a biocompatible, safe and affordable source of preventive/curative approaches. Due to cultural acceptance and patient compliance, there has been a focus on the use of botanical drugs and phytochemicals for burn wound healing. Keeping in consideration of medicinal herbs and phytochemicals as suitable therapeutic/adjuvant agents for burn wound management, this review highlights therapeutic potential of 35 medicinal herbs and 10 phytochemicals. Among these, Elaeis guineensis, Ephedra ciliate and Terminalia avicennioides showed better burn wound healing potential with varied mechanisms such as modulation of TNF-alpha, inflammatory cytokines, nitric oxide, eicosanoids, ROS and leukocyte response. Phytochemicals (oleanolic acid, ursolic acid, kirenol) also showed promising role in burn wound management though various pathways involving such as down regulation of TNF-alpha, IL-6 and inflammatory mediators including plasma proteases and arachidonic acid metabolites. This review provides a pavement for therapeutic/adjuvant use of potential botanical drugs and novel druggable phyto-compounds to target skin burn injury with diverse mechanisms, affordability and safety profile.

Incidence and risk factors for anastomotic bile leakage in hepatic resection with bilioenteric reconstruction - A international multicenter study.

BACKGROUND: Anastomotic leak (AL) after bilioenteric reconstruction (BR) is a feared complication after bile duct resection, especially in combination with liver resection. Literature on surgical outcome is sparse. This study aimed to determine the incidence and risk factors for AL after combined liver and bile duct resection with a focus on operative or endoscopic reinterventions. METHODS: Data from consecutive patients who underwent liver resection and BR between 2004 and 2018 in 11 academic institutions in Europe were collected from prospectively maintained databases. RESULTS: Within 921 patients, AL rate was 5.4% with a 30d mortality of 9.6%. Pringle maneuver (p<0.001),postoperative external biliary (p=0.007) and abdominal drainage (p<0.001) were risk factors for clinically relevant AL. Preoperative biliary drainage (p<0.001) was not associated with a higher rate of AL. AL was more frequent in stented patients (76.5%) compared to PTCD (17.6%) or PTCD+stent (5.9%,p=0.017). AL correlated with increased incidence of postoperative liver failure (p=0.036), cholangitis, hemorrhage and sepsis (all p<0.001). CONCLUSION: This multicenter data provides the largest series to date of LR with BR and could help in the management of these patients which are often challenging and hampering the patients' postoperative course negatively.

The multi-societal European consensus on the terminology, diagnosis and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management. METHODS: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSIONS: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration.

BACKGROUND AND AIMS: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. APPROACH AND RESULTS: Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients. CONCLUSIONS: Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.

Surgical management of suspected gallbladder cancer: The role of intraoperative frozen section for diagnostic confirmation.

BACKGROUND: Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT). METHODS: MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes. RESULTS: A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p < 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically. CONCLUSIONS: The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time.

Bromocriptine therapy: Review of mechanism of action, safety and tolerability.

Bromocriptine is a sympatholytic dopamine D2 receptor agonist with remarkable bioactivities. It has been used clinically as a prescription drug for more than 30 years to treat hyperprolactinemia associated conditions, Parkinson's disease, acromegaly, prolactinomas and other pituitary hormone dependent adenomas and recently, diabetes mellitus as well as various other disorders. Long-term treatment with bromocriptine has minimal or no harmful effects on renal, hepatic, cardiac or hematologic functions. This review article was planned to study the hypothetical and proposed mechanism of action as well as provide a brief discussion about its safety issues and tolerability. Bromocriptine represents an attractive option with high efficacy and safety profile for hyperprolactinemia-associated conditions, acromegaly, parkinsonism, type 2 diabetes mellitus and various other diseases in a variety of dosage forms for best possible beneficial effects. It appeared to be an effective and safe addition to the pharmacopoeia of drugs for the treatment of a vast variety of diseases as monotherapy or in combination with other drugs.

A Multi-Tier Trust-Based Security Mechanism for Vehicular Ad-Hoc Network Communications.

Securing communications in vehicle ad hoc networks is crucial for operations. Messages exchanged in vehicle ad hoc network communications hold critical information such as road safety information, or road accident information and it is essential these packets reach their intended destination without any modification. A significant concern for vehicle ad hoc network communications is that malicious vehicles can intercept or modify messages before reaching their intended destination. This can hamper vehicle ad hoc network operations and create safety concerns. The multi-tier trust management system proposed in this paper addresses the concern of malicious vehicles in the vehicle ad hoc network using three security tiers. The first tier of the proposed system assigns vehicles in the vehicle ad hoc network a trust value based on behaviour such as processing delay, packet loss and prior vehicle behavioural history. This will be done by selecting vehicles as watchdogs to observe the behaviour of neighbouring vehicles and evaluate the trust value. The second tier is to protect the watchdogs, which is done by watchdogs' behaviour history. The third security tier is to protect the integrity of data used for trust value calculation. Results show that the proposed system is successful in identifying malicious vehicles in the VANET. It also improves the packet delivery ratio and end-to-end delay of the vehicle ad hoc network in the presence of malicious vehicles.