Development and Validation of a Predictive Risk Score for Blood Transfusion in Patients Undergoing Curative-Intent Surgery for Intrahepatic Cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Among patients undergoing liver resection for intrahepatic cholangiocarcinoma (ICC), perioperative bleeding requiring blood transfusion is a common complication, yet preoperative identification of patients at risk for transfusion remains challenging. The objective of this study was to develop a preoperative risk score for blood transfusion requirement during surgery for ICC. METHODS: Patients undergoing curative-intent liver surgery for ICC (1990-2020) were identified from a multi-institutional database. A predictive model was developed and validated. An easy-to-use risk calculator was made available online. RESULTS: Among 1420 patients, 300 (21.1%) received an intraoperative transfusion. Independent predictors of transfusion included severe preoperative anemia (OR = 1.65, 95% CI 1.10-2.47), T2 category or higher (OR = 2.00, 95% CI 1.36-3.02), positive lymph nodes (OR = 1.75, 95% CI 1.32-2.32) and major resection (OR = 2.56, 95%CI 1.85-3.58). Receipt of blood transfusion significantly correlated with worse outcomes. The model showed good discriminative ability in both training (AUC = 0.68, 95% CI 0.66-0.72) and bootstrapping validation (C-index = 0.67, 95% CI 0.65-0.70) cohorts. An online risk calculator of blood transfusion requirement was developed (https://catalano-giovanni.shinyapps.io/TransfusionRisk). CONCLUSIONS: Intraoperative blood transfusion was significantly associated with poor postoperative outcomes among patients undergoing surgery for ICC. The identification of patients at high risk of transfusion could improve perioperative patient care and blood resources allocation.

Identification of PRMT5 as a therapeutic target in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified. OBJECTIVE: We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA. DESIGN: We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms. RESULTS: PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions. CONCLUSION: PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.

Machine learning models including preoperative and postoperative albumin-bilirubin score: short-term outcomes among patients with hepatocellular carcinoma.

BACKGROUND: We sought to assess the impact of various perioperative factors on the risk of severe complications and post-surgical mortality using a novel maching learning technique. METHODS: Data on patients undergoing resection for HCC were obtained from an international, multi-institutional database between 2000 and 2020. Gradient boosted trees were utilized to construct predictive models. RESULTS: Among 962 patients who underwent HCC resection, the incidence of severe postoperative complications was 12.7% (n = 122); in-hospital mortality was 2.9% (n = 28). Models that exclusively used preoperative data achieved AUC values of 0.89 (95%CI 0.85 to 0.92) and 0.90 (95%CI 0.84 to 0.96) to predict severe complications and mortality, respectively. Models that combined preoperative and postoperative data achieved AUC values of 0.93 (95%CI 0.91 to 0.96) and 0.92 (95%CI 0.86 to 0.97) for severe morbidity and mortality, respectively. The SHAP algorithm demonstrated that the factor most strongly predictive of severe morbidity and mortality was postoperative day 1 and 3 albumin-bilirubin (ALBI) scores. CONCLUSION: Incorporation of perioperative data including ALBI scores using ML techniques can help risk-stratify patients undergoing resection of HCC.

The differential benefit of laparoscopic over open minor liver resection for lesions situated in the anterolateral or posterosuperior segments.

Background: It is well known that laparoscopic liver surgery can offer advantages over open liver surgery in selected patients. However, what type of procedures can benefit most from a laparoscopic approach has been investigated poorly thus far. The aim of this study is thus to define the extent of advantages of laparoscopic over open liver surgery for lesions in the anterolateral (AL) and posterosuperior (PS) segments. Methods: In this international multicentre retrospective cohort study, laparoscopic and open minor liver resections for lesions in the AL and PS segments were compared after propensity score matching. The differential benefit of laparoscopy over open liver surgery, calculated using bootstrap sampling, was compared between AL and PS resections and expressed as a Delta of the differences. Results: After matching, 3,040 AL and 2,336 PS resections were compared, encompassing open and laparoscopic procedures in a 1:1 ratio. AL and PS laparoscopic liver resections were more advantageous in comparison to open in terms of blood loss, transfusion rate, complications, and length of stay. However, AL resections benefitted more from laparoscopy than PS in terms of overall and severe complications (D-difference were 4.8%, P=0.046 and 3%, P=0.046) and blood loss (D-difference was 195 mL, P<0.001). Similar results were observed in the subset for high-volume centres, while in recent years no significant differences were found in the differential benefit between AL and PS segments. Conclusions: The advantage of laparoscopic over open liver surgery is greater in the AL segments than in the PS segments.

Preoperative platelet count as an independent predictor of long-term outcomes among patients undergoing resection for intrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: An elevated platelet count may reflect neoplastic and inflammatory states, with cytokine-driven overproduction of platelets. The objective of this study was to evaluate the prognostic utility of high platelet count among patients undergoing curative-intent liver surgery for intrahepatic cholangiocarcinoma (ICC). METHODS: An international, multi-institutional cohort was used to identify patients undergoing curative-intent liver resection for ICC (2000-2020). A high platelet count was defined as platelets >300 *109/L. The relationship between preoperative platelet count, cancer-specific survival (CSS), and overall survival (OS) was examined. RESULTS: Among 825 patients undergoing curative-intent resection for ICC, 139 had a high platelet count, which correlated with multifocal disease, lymph nodes metastasis, poor to undifferentiated grade, and microvascular invasion. Patients with high platelet counts had worse 5-year (35.8% vs. 46.7%, p = 0.009) CSS and OS (24.8% vs. 39.8%, p < 0.001), relative to patients with a low platelet count. After controlling for relevant clinicopathologic factors, high platelet count remained an adverse independent predictor of CSS (HR = 1.46, 95% CI 1.02-2.09) and OS (HR = 1.59, 95% CI 1.14-2.22). CONCLUSIONS: High platelet count was associated with worse tumor characteristics and poor long-term CSS and OS. Platelet count represents a readily-available laboratory value that may preoperatively improve risk-stratification of patients undergoing curative-intent liver resection for ICC.

Laparoscopic versus open right hepatectomy for colorectal liver metastases after portal vein embolization: international multicentre study.

BACKGROUND: Laparoscopic liver surgery is increasingly used for more challenging procedures. The aim of this study was to assess the feasibility and oncological safety of laparoscopic right hepatectomy for colorectal liver metastases after portal vein embolization. METHODS: This was an international retrospective multicentre study of patients with colorectal liver metastases who underwent open or laparoscopic right and extended right hepatectomy after portal vein embolization between 2004 and 2020. The perioperative and oncological outcomes for patients who underwent laparoscopic and open approaches were compared using propensity score matching. RESULTS: Of 338 patients, 84 patients underwent a laparoscopic procedure and 254 patients underwent an open procedure. Patients in the laparoscopic group less often underwent extended right hepatectomy (18% versus 34.6% (P = 0.004)), procedures in the setting of a two-stage hepatectomy (42% versus 65% (P < 0.001)), and major concurrent procedures (4% versus 16.1% (P = 0.003)). After propensity score matching, 78 patients remained in each group. The laparoscopic approach was associated with longer operating and Pringle times (330 versus 258.5 min (P < 0.001) and 65 versus 30 min (P = 0.001) respectively) and a shorter length of stay (7 versus 8 days (P = 0.011)). The R0 resection rate was not different (71% for the laparoscopic approach versus 60% for the open approach (P = 0.230)). The median disease-free survival was 12 (95% c.i. 10 to 20) months for the laparoscopic approach versus 20 (95% c.i. 13 to 31) months for the open approach (P = 0.145). The median overall survival was 28 (95% c.i. 22 to 48) months for the laparoscopic approach versus 42 (95% c.i. 35 to 52) months for the open approach (P = 0.614). CONCLUSION: The advantages of a laparoscopic over an open approach for (extended) right hepatectomy for colorectal liver metastases after portal vein embolization are limited.

Single large hepatocellular carcinoma > 5 cm with surgical indication: is it mandatory a major hepatectomy? a propensity-score weighted analysis.

PURPOSE: Single large hepatocellular carcinoma >5cm (SLHCC) traditionally requires a major liver resection. Minor resections are often performed with the goal to reduce morbidity and mortality. Aim of the study was to establish if a major resection should be considered the best treatment for SLHCC or a more limited resection should be preferred. METHODS: A multicenter retrospective analysis of the HE.RC.O.LE.S. Group register was performed. All collected patients with surgically treated SLHCC were divided in 5 groups of treatment (major hepatectomy, sectorectomy, left lateral sectionectomy, segmentectomy, non-anatomical resection) and compared for baseline characteristics, short and long-term results. A propensity-score weighted analysis was performed. RESULTS: 535 patients were enrolled in the study. Major resection was associated with significantly increased major complications compared to left lateral sectionanectomy, segmentectomy and non-anatomical resection (all p<0.05) and borderline significant increased major complications compared to sectorectomy (p=0.08). Left lateral sectionectomy showed better overall survival compared to major resection (p=0.02), while other groups of treatment resulted similar to major hepatectomy group for the same item. Absence of oncological benefit after major resection and similar outcomes among the 5 groups of treatment was confirmed even in the sub-population excluding patients with macrovascular invasion. CONCLUSION: Major resection was associated to increased major post-operative morbidity without long-term survival benefit; when technically feasible and oncologically adequate, minor resections should be preferred for the surgical treatment of SLHCC.

Development of an artificial intelligence-based model to predict early recurrence of neuroendocrine liver metastasis after resection.

PURPOSE: We sought to develop an artificial intelligence (AI)-based model to predict early recurrence (ER) after curative-intent resection of neuroendocrine liver metastases (NELMs). METHODS: Patients with NELM who underwent resection were identified from a multi-institutional database. ER was defined as recurrence within 12 months of surgery. Different AI-based models were developed to predict ER using 10 clinicopathologic factors. RESULTS: Overall, 473 patients with NELM were included. Among 284 patients with recurrence (60.0%), 118 patients (41.5%) developed an ER. An ensemble AI model demonstrated the highest area under receiver operating characteristic curves of 0.763 and 0.716 in the training and testing cohorts, respectively. Maximum diameter of the primary neuroendocrine tumor, NELM radiologic tumor burden score, and bilateral liver involvement were the factors most strongly associated with risk of NELM ER. Patients predicted to develop ER had worse 5-year recurrence-free survival and overall survival (21.4% vs 37.1% [P = .002] and 61.6% vs 90.3% [P = .03], respectively) than patients not predicted to recur. An easy-to-use tool was made available online: (https://altaf-pawlik-nelm-earlyrecurrence-calculator.streamlit.app/). CONCLUSION: An AI-based model demonstrated excellent discrimination to predict ER of NELM after resection. The model may help identify patients who can benefit the most from curative-intent resection, risk stratify patients according to prognosis, as well as guide tailored surveillance and treatment decisions including consideration of nonsurgical treatment options.

Impact of metformin, statin, aspirin and insulin on the prognosis of uHCC patients receiving first line Lenvatinib or Atezolizumab plus Bevacizumab.

Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Cornerstones and divergencies in the implementation and use of liver hypertrophy techniques: results from a nationwide survey for the set-up of the prospective registry.

BACKGROUND: The aim of this national survey on liver hypertrophy techniques was to track the trends of their use and implementation in Italy and to detect analogies and heterogeneities among centers. METHODS: In December 2022, Italian centers with liver resection activity were specifically contacted and asked to fill an online questionnaire composed of 6 sections including a total of 51 questions. RESULTS: 46 Italian centers filled the questionnaire. The proportion of major/total number of liver resections was 27% and the use of hypertrophy techniques was required in 6,2% of cases. The most frequent reason of drop out was disease progression in 58.5% of cases. Most frequently used techniques were PVE and ALPPS with an increasing use of hepatic venous deprivation (HVD). Heterogeneous answers were provided regarding the cutoff values to indicate the need for hypertrophy techniques. Criteria to allocate a patient to different hypertrophy techniques are not standardized. CONCLUSIONS: The use of hypertrophy techniques is deep-rooted in Italy, documenting the established value of their role in improving resectability rate. While an evolution of techniques is detectable, still significant heterogeneity is perceived in terms of cutoff values, indications and managing protocols.

Preoperative and postoperative predictive models of early recurrence for colorectal liver metastases following chemotherapy and curative-intent one-stage hepatectomy.

INTRODUCTION: Accurate prediction of patients at risk for early recurrence (ER) among patients with colorectal liver metastases (CRLM) following preoperative chemotherapy and hepatectomy remains limited. METHODS: Patients with CRLM who received chemotherapy prior to undergoing curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with ER, and an online calculator was developed and validated. RESULTS: Among 768 patients undergoing preoperative chemotherapy and curative-intent resection, 128 (16.7 %) patients had ER. Multivariable Cox analysis demonstrated that Eastern Cooperative Oncology Group Performance status ≥1 (HR 2.09, 95%CI 1.46-2.98), rectal cancer (HR 1.95, 95%CI 1.35-2.83), lymph node metastases (HR 2.39, 95%CI 1.60-3.56), mutated Kirsten rat sarcoma oncogene status (HR 1.95, 95%CI 1.25-3.02), increase in tumor burden score during chemotherapy (HR 1.51, 95%CI 1.03-2.24), and bilateral metastases (HR 1.94, 95%CI 1.35-2.79) were independent predictors of ER in the preoperative setting. In the postoperative model, in addition to the aforementioned factors, tumor regression grade was associated with higher hazards of ER (HR 1.91, 95%CI 1.32-2.75), while receipt of adjuvant chemotherapy was associated with lower likelihood of ER (HR 0.44, 95%CI 0.30-0.63). The discriminative accuracy of the preoperative (training: c-index: 0.77, 95%CI 0.72-0.81; internal validation: c-index: 0.79, 95%CI 0.75-0.82) and postoperative (training: c-index: 0.79, 95%CI 0.75-0.83; internal validation: c-index: 0.81, 95%CI 0.77-0.84) models was favorable (https://junkawashima.shinyapps.io/CRLMfollwingchemotherapy/). CONCLUSIONS: Patient-, tumor- and treatment-related characteristics in the preoperative and postoperative setting were utilized to develop an online, easy-to-use risk calculator for ER following resection of CRLM.

Long-term survivors after curative-intent resection for intrahepatic cholangiocarcinoma.

OBJECTIVES: The objective of the current study was to characterize prognostic factors related to long-term recurrence-free survival after curative-intent resection of intrahepatic cholangiocarcinoma (ICC). METHODS: Data on patients who underwent curative-intent resection for ICC between 2000 and 2020 were collected from an international multi-institutional database. Prognostic factors were investigated among patients who recurred within 5 years versus long-term survivors who survived more than 5 years with no recurrence. RESULTS: Among 635 patients who underwent curative-intent resection for ICC, 104 (16.4%) patients were long-term survivors with no recurrence beyond 5 years after surgery. Patients who survived for more than 5 years with no recurrence were more likely to have less aggressive tumor features, as well as have undergone an R0 resection versus patients who recurred within 5 years after resection. On multivariable analysis, tumor size (>5 cm) (HR: 1.535, 95% CI: 1.254-1.879), satellite lesions (HR: 1.253, 95% CI: 1.003-1.564), and lymph node metastasis (HR: 1.733, 95% CI: 1.349-2.227) were independently associated with recurrence within 5 years. Patients who recurred beyond 5 years (n = 23), 2-5 years (n = 60), and within 2 years (n = 471) had an incrementally worse post-recurrence survival (PRS, 28.0 vs. 20.0 vs. 12.0 months, p = 0.032). Among patients with N0 status, tumor size (>5 cm) (HR: 1.612, 95% CI: 1.087-2.390) and perineural invasion (PNI) (HR: 1.562,95% CI: 1.081-2.255) were risk factors associated with recurrence. Among patients with N1 disease, only a minority (5/128, 3.9%) of patients survived with no recurrence to 5 years. CONCLUSION: Roughly 1 in 6 patients survived for more than 5 years with no recurrence following curative-intent resection of ICC. Among N0 patients, tumor recurrence was associated with tumor size and PNI. Only a small subset of N1 patients experienced long-term survival.

Robotic Major Hepatectomy in Elderly Patient.

BACKGROUND: the role of minimally invasive liver surgery has been progressively developed, with the practice increasing in safety and feasibility also with respect to major liver resections. The aim of this study was to analyze the feasibility and safety of major liver resection in elderly patients. METHODS: data from a multicentric retrospective database including 1070 consecutive robotic liver resections in nine European hospital centers were analyzed. Among these, 131 were major liver resections. Patients were also divided in two groups (<65 years old and ≥65 years old) and perioperative data were compared between the two groups. RESULTS: a total of 131 patients were included in the study. Operative time was 332 ± 125 min. Postoperative overall complications occurred in 27.1% of patients. Severe complications (Clavien Dindo ≥ 3) were 9.9%. Hospital stay was 6.6 ± 5.3 days. Patients were divided into two groups based on their age: 75 patients < 65 years old and 56 patients ≥ 65 years old. Prolonged pain, lung infection, intensive care stay, and 90-day readmission were worse in the elderly group. The two groups were matched for ASA and Charlson comorbidity score and, after statistical adjustment, postoperative data were similar between two groups. CONCLUSIONS: robotic major liver resection in elderly patients was associated with satisfying short-term outcomes.

Harmonizing Definitions and Perspectives in Extreme Liver Surgery: A Delphi Experts Consensus.

OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.

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.

Augmented reality improving intraoperative navigation in minimally invasive liver surgery: an interplay between 3D reconstruction and indocyanine green.

Technology have helped surgeons to increase MILS feasibility, so that currently liver surgery evolution is strongly based on technological advances and the same trend is expected even further soon. Aim of the present technical report is to provide insights regarding the possible interplay between 3D reconstructions based on augmented reality and intraoperative navigation by indocyanine green fluorescence. Augmented reality methods based on reconstructions created through artificial intelligence interact synergistically. The better the understanding of the anatomy and characteristics of the lesion, the more accurate the preoperative planning may be scheduled. On the other hand, the better the intraoperative navigation, the more reproducible the preoperative planning becomes.

Prognostic significance of postoperative complications for patients with hepatocellular carcinoma relative to alpha-feto protein and tumor burden score.

BACKGROUND: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test. RESULTS: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20). CONCLUSION: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics.

Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.