Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications.

Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.

Macroscopic Characterization of Hepatocellular Carcinoma: An Underexploited Source of Prognostic Factors.

The macroscopic appearance of a tumor such as hepatocellular carcinoma (HCC) may be defined as its phenotype which is de facto dictated by its genotype. Therefore, macroscopic characteristics of HCC are unlikely random but rather reflect genomic traits of cancer, presumably acting as a valuable source of information that can be retrieved and exploited to infer prognosis. This review aims to provide a comprehensive overview of the available data on the prognostic value of macroscopic characterization in HCC. A total of 57 studies meeting eligible criteria were identified, including patients undergoing liver resection (LR; 47 studies, 83%) or liver transplant (LT; 9 studies, 16%). The following macroscopic variables were investigated: tumor size (n = 42 studies), number of nodules (n = 28), vascular invasion (n = 24), bile duct invasion (n = 6), growth pattern (n = 15), resection margin (n = 11), tumor location (n = 6), capsule (n = 2) and satellite (n = 1). Although the selected studies provided insightful data with notable prognostic performances, a lack of standardization and substantial gaps were noted in the report and the analysis of gross findings. This topic remains incompletely covered. While the available studies underscored the value of macroscopic variables in HCC prognostication, important lacks were also observed. Macroscopic characterization of HCC is likely an underexploited source of prognostic factors that must be actively explored by future multidisciplinary research.

Enhanced recovery after liver surgery in cirrhotic patients: a systematic review and meta-analysis.

BACKGROUND: Few studies have assessed enhanced recovery after surgery (ERAS) in liver surgery for cirrhotic patients. The present meta-analysis assessed the impact of ERAS pathways on outcomes after liver surgery in cirrhotic patients compared to standard care. METHODS: A literature search was performed on PubMed/MEDLINE, Embase, and the Cochrane Library. Studies comparing ERAS protocols versus standard care in cirrhotic patients undergoing liver surgery were included. The primary outcome was post-operative complications, while secondary outcomes were mortality rates, length of stay (LoS), readmissions, reoperations, and liver failure rates. RESULTS: After evaluating 41 full-text manuscripts, 5 articles totaling 646 patients were included (327 patients in the ERAS group and 319 in the non-ERAS group). Compared to non-ERAS care, ERAS patients had less risk of developing overall complications (OR 0.43, 95% CI 0.31-0.61, p < 0.001). Hospitalization was on average 2 days shorter for the ERAS group (mean difference - 2.04, 95% CI - 3.19 to - 0.89, p < 0.001). Finally, no difference was found between both groups concerning 90-day post-operative mortality and rates of reoperations, readmissions, and liver failure. CONCLUSION: In cirrhotic patients, ERAS protocol for liver surgery is safe and decreases post-operative complications and LoS. More randomized controlled trials are needed to confirm the results of the present analysis.

Tc-99m mebrofenin hepatobiliary scintigraphy to assess future liver remnant function before major liver surgery.

BACKGROUND AND OBJECTIVES: Assessment of liver function is paramount before hepatectomy. This study aimed to assess future liver remnant function (FLR-F) using hepatobiliary scintigraphy (HBS) and to compare it to FLR volume (FLR-V) in the prediction of posthepatectomy liver failure (PHLF). The impact of volume and function gains were also assessed in patients undergoing portal vein embolization (PVE) or liver venous deprivation (LVD). METHODS: All consecutive patients undergoing major hepatectomy between 02/2018 and 09/2021 with preoperative HBS were included. FLR-V was expressed as percentage of total liver volume and analyzed using preoperative computed tomography. FLR-V and FLR-F gains after embolization were expressed in percentage. Receiver operating characteristic analysis was performed to compare both methods in predicting PHLF. RESULTS: Thirty-six patients were included. PVE and LVD were performed in 4 (11%) and 28 patients (78%), respectively. Overall, PHLF occurred in eight patients (22%). FLR-F gain after embolization showed significant ability to predict PHLF (area under the curve [AUC] = 0.789), with cut-off value of 150% showing a sensitivity of 1.00, a specificity of 0.42, and a negative predictive value of 1.00. CONCLUSION: Preoperative HBS shows a high sensitivity to predict PHLF when HBS is performed twice to measure the function gain after venous embolization.

[Management of acute cholecystitis]. / Prise en charge de la cholécystite aiguë.

Acute cholecystitis is an inflammation of the gallbladder most often related to gallstones. The diagnostic and severity criteria are well described by the Tokyo criteria. Early laparoscopic cholecystectomy remains the treatment of choice. It can also be performed in elderly patients and in pregnant women during any trimester. For patients not eligible for surgery, percutaneous or echo-endoscopic gallbladder drainage (EUS-GBD) are effective treatment alternatives. The management of acute cholecystitis must therefore be adapted to each patient by carefully evaluating the risks and benefits associated with surgery.

La cholécystite aiguë est une inflammation de la vésicule biliaire le plus souvent liée à des calculs biliaires. Les critères diagnostiques et de sévérité sont bien décrits par les critères de Tokyo. La cholécystectomie laparoscopique précoce reste le traitement de choix. Elle peut être également réalisée chez les patients âgés et chez les femmes enceintes pendant n'importe quel trimestre. Pour les patients non éligibles à la chirurgie, les drainages de la vésicule biliaire par voie percutanée ou échoendoscopique (EUS-GBD) sont des alternatives thérapeutiques efficaces. La prise en charge de la cholécystite aiguë doit donc être adaptée à chaque patient en évaluant de façon attentive les risques et bénéfices associés à la chirurgie.

[Novelties on the management of alveolar echinococcosis]. / Nouveautés dans la prise en charge de l'échinococcose alvéolaire.

Alveolar echinococcosis is an endemic parasitosis in Switzerland. This pathology mainly infects the liver and develops similarly as a malignant tumor with its ability to spread into the hepatic parenchyma and its capacity of developing distant lesions via hematogenous dissemination. Treatment is based on complete surgical resection coupled with albendazole treatment. Recently, ex vivo liver resections with auto-transplantation have been shown to be feasible in case of end-stage alveolar echinococcosis. Moreover, new biomarkers such as programmed death-ligand 1 (PD-L1), a protein with immunomodulation property, have shown their potential impact on the treatment and follow-up of patients with alveolar echinococcosis.

L'échinococcose alvéolaire est une parasitose endémique en Suisse. Cette pathologie touche principalement le foie et se développe telle une tumeur maligne, par sa propension à envahir le parenchyme hépatique et par sa capacité à développer des lésions à distance par voie hématogène. Le traitement repose sur une exérèse chirurgicale complète couplée à un traitement d'albendazole. Récemment, des techniques de résection hépatique ex vivo avec auto-transplantation ont montré leur faisabilité en cas d'échinococcose alvéolaire avancée. De plus, de nouveaux marqueurs, comme le programmed death-ligand 1 (PD-L1), protéine jouant un rôle dans l'immunomodulation, ont montré leur potentiel impact pour le traitement et le suivi des patients atteints d'échinococcose alvéolaire.

Tumor burden in patients with early and intermediate-stage hepatocellular carcinoma undergoing liver resection: a retrospective multicenter study on clinical and oncological outcomes.

BACKGROUND: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, liver resection (LR) is recommended for early-stage (BCLC-A) hepatocellular carcinoma (HCC) but not for intermediate-stage (BCLC-B). This study aimed to assess the outcomes of LR in these patients using a subclassification tumour burden score (TBS). METHODS: All consecutive patients that underwent LR for BCLC-A and BCLC-B HCC between 01/2010 and 12/2020 in 4 tertiary referral centers were included. Clinical outcomes and overall survival (OS) were assessed in relation to TBS and BCLC stages. RESULTS: Among 612 patients included, 562 were classified as BCLC-A and 50 as BCLC-B. The incidence of overall postoperative complications (56.0 vs 41.5%, p = 0.053) and mortality (0 vs 1.6%, p = 1.000) were similar between BCLC-A and BCLC-B patients. OS was significantly higher for BCLC A/low TBS than BCLC B/low TBS (p = 0.009), while patients with medium and high TBS had similar OS, irrespective of BCLC stage (respectively p = 0.103 and p = 0.343). CONCLUSIONS: Patients with medium and high TBS had comparable OS and DFS, irrespective of BCLC A or B stage, and postoperative morbidity was comparable. These results highlight the need for refinement of the BCLC staging system, and LR could be considered for selected intermediate stage (BCLC-B) according to the tumour burden.

Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations 2022.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been widely applied in liver surgery since the publication of the first ERAS guidelines in 2016. The aim of the present article was to update the ERAS guidelines in liver surgery using a modified Delphi method based on a systematic review of the literature. METHODS: A systematic literature review was performed using MEDLINE/PubMed, Embase, and the Cochrane Library. A modified Delphi method including 15 international experts was used. Consensus was judged to be reached when >80% of the experts agreed on the recommended items. Recommendations were based on the Grading of Recommendations, Assessment, Development and Evaluations system. RESULTS: A total of 7541 manuscripts were screened, and 240 articles were finally included. Twenty-five recommendation items were elaborated. All of them obtained consensus (>80% agreement) after 3 Delphi rounds. Nine items (36%) had a high level of evidence and 16 (64%) a strong recommendation grade. Compared to the first ERAS guidelines published, 3 novel items were introduced: prehabilitation in high-risk patients, preoperative biliary drainage in cholestatic liver, and preoperative smoking and alcohol cessation at least 4 weeks before hepatectomy. CONCLUSIONS: These guidelines based on the best available evidence allow standardization of the perioperative management of patients undergoing liver surgery. Specific studies on hepatectomy in cirrhotic patients following an ERAS program are still needed.

An algorithm based on the postoperative decrease of albumin (ΔAlb) to anticipate complications after liver surgery.

BACKGROUND: Perioperative decrease of albumin (ΔAlb) appeared as a promising predictor of complications after digestive surgery, but its role after liver surgery remains unclear. This study aimed to analyze whether and how ΔAlb can be used to predict complications after liver surgery. METHODS: A bicentric retrospective analysis of patients undergoing liver surgery (2010-2016) was performed, following TRIPOD guidelines. The preoperative and postoperative difference of albumin was calculated on POD 0 and defined as ΔAlb. Patients with any missing variable were excluded. The primary endpoint was overall complications according to the Clavien classification. A multiparametric algorithm based on ΔAlb was generated to optimize prediction performance. RESULTS: A total of 110 patients were analyzed. At least one complication occurred in 66 (60%) patients. Patients with and without complication showed a ΔAlb of 15.8 vs. 9.5 g/L (p<0.001). Area under ROC curve (AUC) of ΔAlb was 0.75 (p<0.01.). The ΔAlb-based algorithm showed an AUC of 0.84 (p<0.01), significantly improving performance (p=0.03). Multivariable analysis identified ΔAlb as independent predictor of complications (HR, 1.12; 95% CI, 1.01-1.07; p = 0.002). CONCLUSIONS: ΔAlb appeared as a promising predictor independently associated with the risk of complication after liver surgery. The study presents a novel decision-tree based on ΔAlb to anticipate complications.

Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma?

Liver transplant (LT) is the most favorable treatment option for patients with early stage hepatocellular carcinoma (HCC). Numerous attempts have been pursued to establish eligibility criteria and select HCC patients for LT, leading to various systems that essentially integrate clinico-morphological variables. Lacking of sufficient granularity to recapitulate the biological complexity of the disease, all these alternatives display substantial limitations and are thus undeniably imperfect. Liquid biopsy, defined as the molecular analysis of circulating analytes released by a cancer into the bloodstream, was revealed as an incomparable tool in the management of cancers, including HCC. It appears as an ideal candidate to refine selection criteria of LT in HCC. The present comprehensive review analyzed the available literature on this topic. Data in the field, however, remain scarce with only 17 studies. Although rare, these studies provided important and encouraging findings highlighting notable prognostic values and supporting the contribution of liquid biopsy in this specific clinical scenario. These results underpinned the critical and urgent need to intensify and accelerate research on liquid biopsy, in order to determine whether and how liquid biopsy may be integrated in the decision-making of LT in HCC.

Early enteral vs. oral nutrition after Whipple procedure: Study protocol for a multicentric randomized controlled trial (NUTRIWHI trial).

Background: Malnutrition has been shown to be a risk factor for postoperative complications after pancreatoduodenectomy (PD). In addition, patients needing a PD, such as patients with pancreatic cancer or chronic pancreatitis, often are malnourished. The best route of postoperative nutrition after PD remains unknown. The aim of this randomized controlled trial is to evaluate if early postoperative enteral nutrition can decrease complications after PD compared to oral nutrition. Methods: This multicenter, open-label, randomized controlled trial will include 128 patients undergoing PD with a nutritional risk screening ≥3. Patients will be randomized 1:1 using variable block randomization stratified by center to receive either early enteral nutrition (intervention group) or oral nutrition (control group) after PD. Patients in the intervention group will receive enteral nutrition since the first night of the operation (250 ml/12 h), and enteral nutrition will be increased daily if tolerated until 1000 ml/12 h. The primary outcome will be the Comprehensive Complication Index (CCI) at 90 days after PD. Discussion: This study with its multicentric and randomized design will permit to establish if early postoperative enteral nutrition after PD improves postoperative outcomes compared to oral nutrition in malnourished patients. Clinical trial registration: https://clinicaltrials.gov/(NCT05042882) Registration date: September 2021.

Basic Science with Preclinical Models to Investigate and Develop Liquid Biopsy: What Are the Available Data and Is It a Fruitful Approach?

The molecular analysis of circulating analytes (circulating tumor-DNA (ctDNA), -cells (CTCs) and -RNA (ctRNA)/exosomes) deriving from solid tumors and detected in the bloodstream-referred as liquid biopsy-has emerged as one of the most promising concepts in cancer management. Compelling data have evidenced its pivotal contribution and unique polyvalence through multiple applications. These data essentially derived from translational research. Therewith, data on liquid biopsy in basic research with preclinical models are scarce, a concerning lack that has been widely acknowledged in the field. This report aimed to comprehensively review the available data on the topic, for each analyte. Only 17, 17 and 2 studies in basic research investigated ctDNA, CTCs and ctRNA/exosomes, respectively. Albeit rare, these studies displayed noteworthy relevance, demonstrating the capacity to investigate questions related to the biology underlying analytes release that could not be explored via translational research with human samples. Translational, clinical and technological sectors of liquid biopsy may benefit from basic research and should take note of some important findings generated by these studies. Overall, results underscored the need to intensify the efforts to conduct future studies on liquid biopsy in basic research with new preclinical models.

Association between CT-Based Preoperative Sarcopenia and Outcomes in Patients That Underwent Liver Resections.

This retrospective observational study aimed to evaluate whether preoperative sarcopenia, assessed by CT imaging, was associated with postoperative clinical outcomes and overall survival in patients that underwent liver resections. Patients operated on between January 2014 and February 2020 were included. The skeletal muscle index (SMI) was measured at the level of the third lumbar vertebra on preoperative CT scans. Preoperative sarcopenia was defined based on pre-established SMI cut-off values. The outcomes were postoperative morbidity, length of hospital stay (LOS), and overall survival. Among 355 patients, 212 (59.7%) had preoperative sarcopenia. Patients with sarcopenia were significantly older (63.5 years) and had significantly lower BMIs (23.9 kg/m2) than patients without sarcopenia (59.3 years, p < 0.01, and 27.7 kg/m2, p < 0.01, respectively). There was no difference in LOS (8 vs. 8 days, p = 0.75), and the major complication rates were comparable between the two groups (11.2% vs. 11.3%, p = 1.00). The median overall survival times were comparable between patients with sarcopenia and those without sarcopenia (15 vs. 16 months, p = 0.87). Based on CT assessment alone, preoperative sarcopenia appeared to have no impact on postoperative clinical outcomes or overall survival in patients that underwent liver resections. Future efforts should also consider muscle strength and physical performance, in addition to imaging, for preoperative risk stratification.

Triple cancer of gallbladder, common bile duct and papilla of Vater: Report of a case and review of literature.

INTRODUCTION AND IMPORTANCE: Synchronous malignancies of gallbladder and biliary tree are together rare entity whose pathogenesis is yet unknown. We report the case of a triple synchronous cancer of 3 distinct location: gallbladder, common bile duct (CBD) and papilla of Vater. CASE PRESENTATION: An 84-years-old woman, was admitted to our Hospital with clinics features of obstructive jaundice. Dilatation of the biliary tree and CBD without evidence of gallstones was seen at US. CT scan confirmed distal CBD obstruction. An endo-US showed a nodule of the head of pancreas infiltrating the lower CBD. Finally, hepatic-MRI displayed a gallbladder malignancy with invasion of CBD. Preoperative staging showed 3 diagnostic suspicions: carcinoma of CBD on CT, pancreatic carcinoma on endo-US and malignancy of gallbladder on MRI. A cephalic duodenopancreatectomy and radical gallbladder resection was performed. Final pathology revealed 3 distinct location of moderately differentiated adenocarcinomas: Gallbladder, CBD and Vater's papilla. Microscopic examination didn't detect any direct continuity between the 3 tumors. Metastases were identified in the pancreaticoduodenal, peri-hepatic and peri-gastric lymph nodes. CLINICAL DISCUSSION: Literature displayed 22 cases of synchronous malignancies of gallbladder and CBD and 1 case of triple cancer with associated Vater's papilla carcinoma. In most of these cases, an association with an anomalous pancreatic-bile duct junction was reported. Although the real incidence remain unknown, it was reported to occur in 5-10% of CBD cancers. CONCLUSION: Suspicion of such combination of cancer should be remembered, especially when preoperative investigations don't allow a precise localization of tumor in the biliary tree.

Probability of Postoperative Complication after Liver Resection: Stratification of Patient Factors,Operative Complexity, and Use of Enhanced Recovery after Surgery.

BACKGROUND: The current study aimed to assess the performance of the 3-level complexity classification that stratified liver resection procedures into 3 complexity grades (grade I, low; grade II, intermediate; and grade III, high complexity) and to evaluate whether the Enhanced Recovery after Surgery (ERAS) protocol improves postoperative outcomes for each complexity grade. STUDY DESIGN: Consecutive patients undergoing open liver resection and laparoscopic liver resection at Lausanne University Hospital during 2010 to 2020 were assessed. RESULTS: A total of 437 patients were included. Operative time, estimated blood loss, and length of hospital stay increased significantly, with a stepwise increase of the grades from I to III in open liver resection and laparoscopic liver resection (all, p < 0.05). The same trend for Comprehensive Complication Index was found in open liver resection (p < 0.005). Age (p = 0.004), 3-level complexity classification (grade II vs I; p = 0.001; grade III vs I; p < 0.001), no use of the ERAS protocol (p = 0.016), and biliary reconstruction (p < 0.001) were significant predictors for postoperative complication, defined as Comprehensive Complication Index ≥ 26.2 in a multivariable logistic regression analysis. The prediction model incorporating the 4 factors had a calculated Concordance Index of 0.735 and 0.742 based on the bootstrapping method. The use of ERAS protocol was associated with lower probability of postoperative complication for each complexity grade and age. CONCLUSIONS: The use of ERAS protocol can decrease the probability of postoperative complication for each surgical complexity of liver resection and patient age. This finding emphasized the importance of tailoring perioperative management according to surgical complexity and patient age to improve outcomes after liver resection.

[Preoperative liver venous deprivation]. / Embolisation portale et sus-hépatique combinée avant hépatectomie ma.

Some hepato-biliary cancers require major liver resections. Post hepatectomy liver failure is a complication that occurs when the remnant liver cannot maintain its synthetic and excretory functions. To overcome this issue, portal vein embolization has been developed to induce future remnant liver hypertrophy preoperatively. However, up to 20% of patients cannot proceed to the hepatectomy due to insufficient hypertrophy or tumor progression in the interval between the embolization and the planned surgery. Liver venous deprivation (LVD) is a technique that combine ipsilateral portal and hepatic vein embolization. With this technique, the hypertrophy seems to be faster and more important, with low complications rate and no mortality associated with the procedure.

Certains cancers hépatobiliaires nécessitent des résections hépatiques majeures. L'insuffisance hépatocellulaire est une complication postopératoire avec un risque de mortalité qui survient lorsque le foie restant ne peut maintenir ses fonctions de synthèse et d'excrétion. L'embolisation de la veine porte a été développée pour induire une hypertrophie du futur foie restant en préopératoire afin d'éviter cette complication. Cependant, 20 % des patients ne peuvent pas bénéficier de l'hépatectomie en raison d'une hypertrophie insuffisante ou d'une progression de la maladie oncologique dans l'intervalle entre l'embolisation et la chirurgie. L'embolisation portale et sus-hépatique combinée est une technique qui consiste à combiner durant le même geste l'embolisation de la veine porte et de la veine sus-hépatique ipsilatérale. Par cette technique, l'hypertrophie semble alors plus rapide et importante, avec peu de complications et aucune mortalité en lien avec la procédure.

An aberrant right hepatic artery arising from the gastroduodenal artery: a pitfall encountered during pancreaticoduodenectomy.

PURPOSE: Among the variations of the right hepatic artery (RHA), the identification of an aberrant RHA arising from the gastroduodenal artery (GDA) is vital for avoiding damage to the RHA during surgery, since ligation of the GDA is necessary during pancreaticoduodenectomy (PD). However, this variation is not frequently reported. The purpose of this study was to focus on an aberrant RHA arising from the GDA, which was not noted in the classifications reported by Michels and Hiatt. METHODS: A total of 574 patients undergoing a PD between Jan 2001 and Dec 2015 at a tertiary care hospital in Switzerland (n = 366) and between Jan 2009 and May 2015 at a hospital in Japan (n = 208) were included in the analysis. Of these, preoperative CT angiography or/and MRI angiography findings were available for 532 patients. We retrospectively analyzed the hepatic artery variations, patient demographics, and surgical outcomes. RESULTS: Among the 532 patients who received a PD, an RHA originating from the GDA was observed in 19 cases (3.5%). Eleven patients (2.1%) had both an aberrant RHA and an aberrant left hepatic artery (LHA) (Hiatt Type 4). Six patients (1.2%) had a replaced CHA arising from the SMA (Hiatt Type 5). We could, therefore, correctly identify the aberration in all cases. CONCLUSIONS: We observed rarely reported but important aberrant RHA variations arising from the GDA. To prevent injury during PD in patients with this type of aberrant RHA, intensive preparations using CT and/or MRI imaging before surgery and intraoperative liver Doppler ultrasonography are considered to be essential.