Using the Comprehensive Complication Index to Rethink the ISGLS Criteria for Post-hepatectomy Liver Failure in an International Cohort of Major Hepatectomies.

OBJECTIVE: To compare different criteria for post-hepatectomy liver failure (PHLF) and evaluate the association between International Study Group of Liver Surgery (ISGLS) PHLF and the Comprehensive Complication Index (CCI)" and 90-day mortality. SUMMARY OF BACKGROUND DATA: PHLF is a serious complication following hepatic resection. Multiple criteria have been developed to characterize PHLF. METHODS: Adults who underwent major hepatectomies at twelve international centers (2010-2020) were included. We identified patients who met criteria for PHLF based on three definitions: 1) ISGLS, 2) Balzan (INR > 1.7 and bilirubin > 2.92mg/dL) or 3) Mullen (peak bilirubin >7mg/dL). We compared the 90-day mortality and major morbidity predicted by each definition. We then used logistic regression to determine the odds of CCI>40 and 90-day mortality associated with ISGLS grades. RESULTS: Among 1646 included patients, 19 (1.1%) met Balzan, 68 (4.1%) met Mullen, and 444 (27.0%) met ISGLS criteria for PHLF. Of the three definitions, the ISGLS criteria best predicted 90-day mortality (AUC = 0.72; sensitivity 69.4%). Patients with ISGLS grades B&C were at increased odds of CCI > 40 (grade B OR 4.0; 95% CI: 2.2-7.2; grade C OR 137.0; 95% CI: 59.2-317.4). Patients with ISGLS grade C were at increased odds of 90-day mortality (OR 113.6; 95% CI: 55.6-232.1). Grade A was not associated with CCI> 40 or 90-day mortality. CONCLUSIONS: In this diverse international cohort of major hepatectomies, ISGLS grade A was not associated with 90-day mortality or high CCI, calling into question the current classification of patients in this group as having clinically significant PHLF.

Development and external validation of a prediction model for overall survival after resection of distal cholangiocarcinoma.

BACKGROUND: Various prognostic factors are associated with overall survival (OS) after resection of distal cholangiocarcinoma (dCCA). The objective of this study was to develop and validate a prediction model for 3-year OS after pancreatoduodenectomy for dCCA. METHODS: The derivation cohort consisted of all patients who underwent pancreatoduodenectomy for dCCA in the Netherlands (2009-2016). Clinically relevant variables were selected based on the Akaike information criterion using a multivariate Cox proportional hazards regression model, with model performance being assessed by concordance index (C-index) and calibration plots. External validation was performed using patients from the Belgium Cancer Registry (2008-2016), and patients from two university hospitals of Southampton (U.K.) and Verona (Italy). RESULTS: Independent prognostic factors for OS in the derivation cohort of 454 patients after pancreatoduodenectomy for dCCA were age (HR 1.02, 95% CI 1.01-1.03), pT (HR 1.43, 95% CI 1.07-1.90) and pN category (pN1: HR 1.78, 95% CI 1.37-2.32; pN2: HR 2.21, 95% CI 1.63-3.01), resection margin status (HR 1.79, 95% CI 1.39-2.29) and tumour differentiation (HR 2.02, 95% CI 1.62-2.53). The prediction model was based on these prognostic factors. The optimism-adjusted C-indices were similar in the derivation cohort (0.69), and in the Belgian (0.66) and Southampton-Verona (0.68) validation cohorts. Calibration was accurate in the Belgian validation cohort (slope = 0.93, intercept = 0.12), but slightly less optimal in the Southampton-Verona validation cohort (slope = 0.88, intercept = 0.32). Based on this model, three risk groups with different prognoses were identified (3-year OS of 65.4%, 33.2% and 11.8%). CONCLUSIONS: The prediction model for 3-year OS after resection of dCCA had reasonable performance in both the derivation and geographically external validation cohort. Calibration slightly differed between validation cohorts. The model is readily available via www. pancreascalculator.com to inform patients from Western European countries on their prognosis, and may be used to stratify patients for clinical trials.

Indocyanine Green Fluorescence Navigation in Liver Surgery: A Systematic Review on Dose and Timing of Administration.

BACKGROUND: Indocyanine green (ICG) fluorescence has proven to be a high potential navigation tool during liver surgery; however, its optimal usage is still far from being standardized. METHODS: A systematic review was conducted on MEDLINE/PubMed for English articles that contained the information of dose and timing of ICG administration until February 2021. Successful rates of tumor detection and liver segmentation, as well as tumor/patient background and imaging settings were also reviewed. The quality assessment of the articles was performed in accordance with the Scottish Intercollegiate Guidelines Network (SIGN). RESULTS: Out of initial 311 articles, a total of 72 manuscripts were obtained. The quality assessment of the included studies revealed usually low; only 9 articles got qualified as high quality. Forty articles (55%) focused on open resections, whereas 32 articles (45%) on laparoscopic and robotic liver resections. Thirty-four articles (47%) described tumor detection ability, and 25 articles (35%) did liver segmentation ability, and the others (18%) did both abilities. Negative staining was reported (42%) more than positive staining (32%). For tumor detection, majority used the dose of 0.5 mg/kg within 14 days before the operation day, and an additional administration (0.02-0.5 mg/kg) in case of longer preoperative interval. Tumor detection rate was reported to be 87.4% (range, 43%-100%) with false positive rate reported to be 10.5% (range, 0%-31.3%). For negative staining method, the majority used 2.5 mg/body, ranging from 0.025 to 25 mg/body. For positive staining method, the majority used 0.25 mg/body, ranging from 0.025 to 12.5 mg/body. Successful segmentation rate was 88.0% (range, 53%-100%). CONCLUSION: The time point and dose of ICG administration strongly needs to be tailored case by case in daily practice, due to various tumor/patient backgrounds and imaging settings.

A machine learning predictive model for recurrence of resected distal cholangiocarcinoma: Development and validation of predictive model using artificial intelligence.

INTRODUCTION: Distal Cholangiocarcinoma (dCCA) represents a challenge in hepatobiliary oncology, that requires nuanced post-resection prognostic modeling. Conventional staging criteria may oversimplify dCCA complexities, prompting the exploration of novel prognostic factors and methodologies, including machine learning algorithms. This study aims to develop a machine learning predictive model for recurrence after resected dCCA. MATERIAL AND METHODS: This retrospective multicentric observational study included patients with dCCA from 13 international centers who underwent curative pancreaticoduodenectomy (PD). A LASSO-regularized Cox regression model was used to feature selection, examine the path of the coefficient and create a model to predict recurrence. Internal and external validation and model performance were assessed using the C-index score. Additionally, a web application was developed to enhance the clinical use of the algorithm. RESULTS: Among 654 patients, LNR (Lymph Node Ratio) 15, neural invasion, N stage, surgical radicality, and differentiation grade emerged as significant predictors of disease-free survival (DFS). The model showed the best discrimination capacity with a C-index value of 0.8 (CI 95 %, 0.77%-0.86 %) and highlighted LNR15 as the most influential factor. Internal and external validations showed the model's robustness and discriminative ability with an Area Under the Curve of 92.4 % (95 % CI, 88.2%-94.4 %) and 91.5 % (95 % CI, 88.4%-93.5 %), respectively. The predictive model is available at https://imim.shinyapps.io/LassoCholangioca/. CONCLUSIONS: This study pioneers the integration of machine learning into prognostic modeling for dCCA, yielding a robust predictive model for DFS following PD. The tool can provide information to both patients and healthcare providers, enhancing tailored treatments and follow-up.

Textbook outcome in patients with biliary duct injury during cholecystectomy.

BACKGROUND: Iatrogenic bile duct injury (BDI) during cholecystectomy is associated with a complex and heterogeneous management owing to the burden of morbidity until their definitive treatment. This study aimed to define the textbook outcomes (TOs) after BDI with the purpose to indicate the ideal treatment and to improve it management. METHODS: We collected data from patients with an BDI between 1990 and 2022 from 27 hospitals. TO was defined as a successful conservative treatment of the iatrogenic BDI or only minor complications after BDI or patients in whom the first repair resolves the iatrogenic BDI without complications or with minor complications. RESULTS: We included 808 patients and a total of 394 patients (46.9%) achieved TO. Overall complications in TO and non-TO groups were 11.9% and 86%, respectively (P < .001). Major complications and mortality in the non-TO group were 57.4% and 9.2%, respectively. The use of end-to-end bile duct anastomosis repair was higher in the non-TO group (23.1 vs 7.8, P < .001). Factors associated with achieving a TO were injury in a specialized center (adjusted odds ratio [aOR], 4.01; 95% CI, 2.68-5.99; P < .001), transfer for a first repair (aOR, 5.72; 95% CI, 3.51-9.34; P < .001), conservative management (aOR, 5.00; 95% CI, 1.63-15.36; P = .005), or surgical management (aOR, 2.45; 95% CI, 1.50-4.00; P < .001). CONCLUSION: TO largely depends on where the BDI is managed and the type of injury. It allows hepatobiliary centers to identify domains of improvement of perioperative management of patients with BDI.

Intraductal papillary neoplasm of the bile duct: The new frontier of biliary pathology.

Intraductal papillary neoplasms of the bile duct (IPNBs) represent a rare variant of biliary tumors characterized by a papillary growth within the bile duct lumen. Since their first description in 2001, several classifications have been proposed, mainly based on histopathological, radiological and clinical features, although no specific guidelines addressing their management have been developed. Bile duct neoplasms generally develop through a multistep process, involving different precursor pathways, ranging from the initial lesion, detectable only microscopically, i.e. biliary intraepithelial neoplasia, to the distinctive grades of IPNB until the final stage represented by invasive cholangiocarcinoma. Complex and advanced investigations, mainly relying on magnetic resonance imaging (MRI) and cholangioscopy, are required to reach a correct diagnosis and to define an adequate bile duct mapping, which supports proper treatment. The recently introduced subclassifications of types 1 and 2 highlight the histopathological and clinical aspects of IPNB, as well as their natural evolution with a particular focus on prognosis and survival. Aggressive surgical resection, including hepatectomy, pancreaticoduodenectomy or both, represents the treatment of choice, yielding optimal results in terms of survival, although several endoscopic approaches have been described. IPNBs are newly recognized preinvasive neoplasms of the bile duct with high malignant potential. The novel subclassification of types 1 and 2 defines the histological and clinical aspects, prognosis and survival. Diagnosis is mainly based on MRI and cholangioscopy. Surgical resection represents the mainstay of treatment, although endoscopic resection is currently applied to nonsurgically fit patients. New frontiers in genetic research have identified the processes underlying the carcinogenesis of IPNB, to identify targeted therapies.

Incidence and Clinical Impact of Bile Leakage after Laparoscopic and Open Liver Resection: An International Multicenter Propensity Score-Matched Study of 13,379 Patients.

BACKGROUND: Despite many developments, postoperative bile leakage (POBL) remains a relatively common postoperative complication after laparoscopic liver resection (LLR) and open liver resection (OLR). This study aimed to assess the incidence and clinical impact of POBL in patients undergoing LLR and OLR in a large international multicenter cohort using a propensity score-matched analysis. STUDY DESIGN: Patients undergoing LLR or OLR for all indications between January 2000 and October 2019 were retrospectively analyzed using a large, international, multicenter liver database including data from 15 tertiary referral centers. Primary outcome was clinically relevant POBL (CR-POBL), defined as Grade B/C POBL. RESULTS: Overall, 13,379 patients met the inclusion criteria and were included in the analysis (6,369 LLR and 7,010 OLR), with 6.0% POBL. After propensity score matching, a total of 3,563 LLR patients were matched to 3,563 OLR patients. In both groups, propensity score matching accounted for similar extent and types of resections. The incidence of CR-POBL was significantly lower in patients after LLR as compared with patients after OLR (2.6% vs 6.0%; p < 0.001). Among the subgroup of patients with CR-POBL, patients after LLR experienced less severe (non-POBL) postoperative complications (10.1% vs 20.9%; p = 0.028), a shorter hospital stay (12.5 vs 17 days; p = 0.001), and a lower 90-day/in-hospital mortality (0% vs 5.4%; p = 0.027) as compared with patients after OLR with CR-POBL. CONCLUSION: Patients after LLR seem to experience a lower rate of CR-POBL as compared with the open approach. Our findings suggest that in patients after LLR, the clinical impact of CR-POBL is less than after OLR.

Survival Study: International Multicentric Minimally Invasive Liver Resection for Colorectal Liver Metastases (SIMMILR-2).

Introduction: Study: International Multicentric Minimally Invasive Liver Resection for Colorectal Liver Metastases (SIMMILR-CRLM) was a propensity score matched (PSM) study that reported short-term outcomes of patients with CRLM who met the Milan criteria and underwent either open (OLR), laparoscopic (LLR) or robotic liver resection (RLR). This study, designated as SIMMILR-2, reports the long-term outcomes from that initial study, now referred to as SIMMILR-1. Methods: Data regarding neoadjuvant chemotherapeutic (NC) and neoadjuvant biological (NB) treatments received were collected, and Kaplan−Meier curves reporting the 5-year overall (OS) and recurrence-free survival (RFS) for OLR, LLR and RLR were created for patients who presented with synchronous lesions only, as there was insufficient follow-up for patients with metachronous lesions. Results: A total of 73% of patients received NC and 38% received NB in the OLR group compared to 70% and 28% in the LLR group, respectively (p = 0.5 and p = 0.08). A total of 82% of patients received NC and 40% received NB in the OLR group compared to 86% and 32% in the RLR group, respectively (p > 0.05). A total of 71% of patients received NC and 53% received NB in the LLR group compared to 71% and 47% in the RLR group, respectively (p > 0.05). OS at 5 years was 34.8% after OLR compared to 37.1% after LLR (p = 0.4), 34.3% after OLR compared to 46.9% after RLR (p = 0.4) and 30.3% after LLR compared to 46.9% after RLR (p = 0.9). RFS at 5 years was 12.1% after OLR compared to 20.7% after LLR (p = 0.6), 33.3% after OLR compared to 26.3% after RLR (p = 0.6) and 22.7% after LLR compared to 34.6% after RLR (p = 0.6). Conclusions: When comparing OLR, LLR and RLR, the OS and RFS were all similar after utilization of the Milan criteria and PSM. Biological agents tended to be utilized more in the OLR group when compared to the LLR group, suggesting that highly aggressive tumors are still managed through an open approach.

Indications, trends, and perioperative outcomes of minimally invasive and open liver surgery in non-obese and obese patients: An international multicentre propensity score matched retrospective cohort study of 9963 patients.

BACKGROUND: Despite the worldwide increase of both obesity and the use of minimally invasive liver surgery (MILS), evidence regarding the safety and eventual benefits of MILS in obese patients is scarce. The aim of this study was therefore to compare the outcomes of non-obese and obese patients (BMI 18.5-29.9 and BMI≥30, respectively) undergoing MILS and OLS, and to assess trends in MILS use among obese patients. METHODS: In this retrospective cohort study, patients operated at 20 hospitals in eight countries (2009-2019) were included and the characteristics and outcomes of non-obese and obese patients were compared. Thereafter, the outcomes of MILS and OLS were compared in both groups after propensity-score matching (PSM). Changes in the adoption of MILS during the study period were investigated. RESULTS: Overall, 9963 patients were included (MILS: n = 4687; OLS: n = 5276). Compared to non-obese patients (n = 7986), obese patients(n = 1977) were more often comorbid, less often received preoperative chemotherapy or had a history of previous hepatectomy, had longer operation durations and more intraoperative blood loss (IOBL), paralleling significantly higher rates of wound- and respiratory-related complications. After PSM, MILS, compared to OLS, was associated, among both non-obese and obese patients, with less IOBL (200 ml vs 320 ml, 200 ml vs 400 ml, respectively), lower rates of transfusions (6.6% vs 12.8%, 4.7% vs 14.7%), complications (26.1% vs 35%, 24.9% vs 34%), bile leaks(4% vs 7%, 1.8% vs 4.9%), liver failure (0.7% vs 2.3%, 0.2% vs 2.1%), and a shorter length of stay(5 vs 7 and 4 vs 7 days). A cautious implementation of MILS over time in obese patients (42.1%-53%, p < .001) was paralleled by stable severe morbidity (p = .433) and mortality (p = .423) rates, despite an accompanying gradual increase in surgical complexity. CONCLUSIONS: MILS is increasingly adopted and associated with perioperative benefits in both non-obese and obese patients.