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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., (© 2024 Wiley Periodicals LLC.)

Introduction: Although up to 50-70% of patients with intrahepatic cholangiocarcinoma (ICC) recur following resection, data to predict post-recurrence survival (PRS) and guide treatment of recurrence are limited., Methods: Patients who underwent resection of ICC between 2000 and 2020 were identified from an international, multi-institutional database. Data on primary disease as well as laboratory and radiologic data on recurrent disease were collected. Factors associated with PRS were examined and a novel scoring system to predict PRS (PRS score) was developed and internally validated., Results: Among 986 individuals who underwent resection for ICC, 588 (59.6%) patients developed recurrence at a median follow up of 20.3 months. Among patients who experienced a recurrence, 97 (16.5%) underwent re-resection/ablation for recurrent ICC; 88 (15.0%) and 403 (68.5%) patients received intra-arterial treatment or systemic chemotherapy/supportive therapy, respectively. Patient American Society of Anesthesiologists (ASA) class > 2 (1 point), primary tumor N1/Nx status (1 point), primary R1 resection margin (1 point), primary tumor G3/G4 grade (1 point), carbohydrate antigen (CA) 19-9 > 37 UI/mL (2 points) at recurrence and carcinoembryonic antigen (CEA) > 5 ng/mL (2 points) at recurrence, as well as recurrent bilateral disease (1 point) and early recurrence (1 point) were included in the PRS score. The PRS score successfully stratified patients relative to PRS and demonstrated strong discriminatory ability (C-index 0.70, 95% confidence interval 0.68-0.72). While a PRS score of 0-3 was associated with a 3-year PRS of 62.5% following resection/ablation for recurrent ICC, a PRS score > 3 was associated with a low 3-year PRS of 35.5% (p = 0.03)., Conclusions: The PRS score demonstrated strong discriminatory ability to predict PRS among patients who had developed recurrence following initial resection of ICC. The PRS score may be a useful tool to guide treatment among patients with recurrent ICC., (© 2024. Society of Surgical Oncology.)

Introduction: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population., Methods: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m 2 , without need for bile duct or vascular resection were chosen as the benchmark group., Results: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0-67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days., Conclusions: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes., (© 2024. The Author(s).)

Introduction: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited., Methods: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases., Results: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients., Conclusions: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC., (© 2024. The Author(s).)

Background: This study aimed to develop a tool based on preoperative factors to predict the risk of perioperative complications based on the Comprehensive Complication Index (CCI) and long-term survival outcomes after liver resection for primary liver cancer., Methods: Patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) undergoing curative-intent hepatectomy between 1990 and 2020 were identified using a multi-institutional international database., Results: Among 1411 patients who underwent curative-intent hepatic resection (HCC: 997, 70.7%; ICC: 414, 29.3%), median patient age was 66.0 years (IQR, 57.0-73.0), and most patients were male (n = 1001, 70.9%). In the postoperative setting, 699 patients (49.5%) experienced a complication; moreover, 112 patients (7.9%) had major complications. Although most patients had a favorable risk complication-overall survival (CompOS) profile (CCI score > 40 risk of <30% and median survival of >5 years: n = 778, 55.1%), 553 patients (39.2%) had an intermediate-risk profile, and 80 patients (5.7%) had a very unfavorable risk profile (CCI score > 40 risk of ≥30% and/or median survival of ≤1.5 years). The areas under the curve of the test and validation cohorts were 0.73 and 0.76, respectively., Conclusion: The CompOS risk model accurately stratified patients relative to short- and long-term risks, identifying a subset of patients at a high risk of major complications and poor overall survival., (Copyright © 2023 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system., Methods: Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed., Results: Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001)., Conclusions: ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy., (© 2023. Society of Surgical Oncology.)

Background: Early-stage intrahepatic cholangiocarcinoma (ICC) is often an indication of curative-intent resection. Although patients with early-stage ICC generally have a better prognosis than individuals with advanced ICC, the incidence and risk factors of recurrence after early-stage ICC remain unclear., Methods: A multi-institutional database was used to identify patients who underwent surgery between 2000 and 2018 for ICC with pathologically confirmed stage I disease. Cox regression analysis was used to identify clinicopathological factors associated with recurrence, and an online prediction model was developed and validated., Results: Of 430 patients diagnosed with stage I ICC, approximately one-half of patients (n = 221, 51.4%) experienced recurrence after curative-intent resection. Among patients with a recurrence, most (n = 188, 85.1%) experienced it within 12 months. On multivariable analysis, carcinoembryonic antigen (hazard ratio [HR], 1.011; 95% CI, 1.004-1.018), systemic immune-inflammation index (HR, 1.036; 95% CI, 1.019-1.056), no lymph nodes evaluated (HR, 1.851; 95% CI, 1.276-2.683), and tumor size (HR, 1.101; 95% CI, 1.053-1.151) were associated with greater hazards of recurrence. A predictive model that included these weighted risk factors demonstrated excellent prognostic discrimination in the test (12-month recurrence-free survival [RFS]: low risk, 80.1%; intermediate risk, 60.3%; high risk, 37.7%; P = .001) and validation (12-month RFS: low risk, 84.5%; intermediate risk, 63.5%; high risk, 47.1%; P = .036) datasets. The online predictive model was made available at https://ktsahara.shinyapps.io/stageI&#95;icc/., Conclusions: Patients with stage I ICC without vascular invasion or lymph node metastasis had a relatively high incidence of recurrence. An online tool can risk stratify patients relative to recurrence risk to identify individuals best suited for alternative treatment approaches., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2023 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: Benchmarking is a process of continuous self-evaluation and comparison with best-in-class hospitals to guide quality improvement initiatives. We sought to define global benchmarks relative to liver resection for malignancy and to assess their achievement in hospitals in the United States., Methods: Patients who underwent curative-intent liver resection for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal or neuroendocrine liver metastases between 2000 and 2019 were identified from an international multi-institutional database. Propensity score matching was conducted to balance baseline characteristics between open and minimally invasive approaches. Best-in-class hospitals were defined relative to the achievement rate of textbook oncologic outcomes and case volume. Benchmark values were established relative to best-in-class institutions. The achievement of benchmark values among hospitals in the National Cancer Database was then assessed., Results: Among 2,624 patients treated at 20 centers, a majority underwent liver resection for hepatocellular carcinoma (n = 1,609, 61.3%), followed by colorectal liver metastases (n = 650, 24.8%), intrahepatic cholangiocarcinoma (n = 299, 11.4%), and neuroendocrine liver metastases (n = 66, 2.5%). Notably, 1,947 (74.2%) patients achieved a textbook oncologic outcome. After propensity score matching, 6 best-in-class hospitals with the highest textbook oncologic outcome rates (≥75.0%) were identified. Benchmark values were calculated for margin positivity (≤11.7%), 30-day readmission (≤4.1%), 30-day mortality (≤1.6%), minor postoperative complications (≤24.7%), severe complications (≤12.4%), and failure to achieve the textbook oncologic outcome (≤22.8%). Among the National Cancer Database hospitals, global benchmarks for margin positivity, 30-day readmission, 30-day mortality, severe complications, and textbook oncologic outcome failure were achieved in 62.9%, 27.1%, 12.1%, 7.1%, and 29.3% of centers, respectively., Conclusion: These global benchmarks may help identify hospitals that may benefit from quality improvement initiatives, aiming to improve patient safety and surgical oncologic outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC)., Aim: To compare the effect of different anti-PD-1 combination therapies as the first-line treatments for uICC., Methods: This study included 318 patients who received chemotherapy alone (Chemo), anti-PD-1 plus chemotherapy (ICI-chemo), anti-PD-1 plus targeted therapy (ICI-target) or anti-PD-1 plus targeted therapy and chemotherapy (ICI-target-chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety., Results: Patients with ICI-chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42-0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39-0.94; p = 0.026), ICI-target (7.2 months; HR: 0.54, 95% CI: 0.36-0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35-0.84; p = 0.006) or ICI-target-chemo (6.9 months; HR: 0.65, 95% CI: 0.47-0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31-0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI-target was not inferior to ICI-chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55-1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51-1.55; p = 0.680). ICI-target-chemo yielded similar prognoses as ICI-chemo (HR for PFS: 1.07, 95% CI: 0.70-1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45-1.31; p = 0.328) and ICI-target (HR for PFS: 1.20, 95% CI: 0.77-1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51-1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings., Conclusions: Among patients with uICC, ICI-chemo or ICI-target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI-target-chemo., (© 2023 John Wiley & Sons Ltd.)

Background: The high incidence of early recurrence after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a detrimental effect on overall survival (OS). Machine-learning models may improve the accuracy of outcome prediction for malignancies., Methods: Patients who underwent curative-intent hepatectomy for ICC were identified using an international database. Three machine-learning models were trained to predict early recurrence (< 12 months after hepatectomy) using 14 clinicopathologic characteristics. The area under the receiver operating curve (AUC) was used to assess their discrimination ability., Results: In this study, 536 patients were randomly assigned to training (n = 376, 70.1%) and testing (n = 160, 29.9%) cohorts. Overall, 270 (50.4%) patients experienced early recurrence (training: n = 150 [50.3%] vs testing: n = 81 [50.6%]), with a median tumor burden score (TBS) of 5.6 (training: 5.8 [interquartile range {IQR}, 4.1-8.1] vs testing: 5.5 [IQR, 3.7-7.9]) and metastatic/undetermined nodes (N1/NX) in the majority of the patients (training: n = 282 [75.0%] vs testing n = 118 [73.8%]). Among the three different machine-learning algorithms, random forest (RF) demonstrated the highest discrimination in the training/testing cohorts (RF [AUC, 0.904/0.779] vs support vector machine [AUC, 0.671/0.746] vs logistic regression [AUC, 0.668/0.745]). The five most influential variables in the final model were TBS, perineural invasion, microvascular invasion, CA 19-9 lower than 200 U/mL, and N1/NX disease. The RF model successfully stratified OS relative to the risk of early recurrence., Conclusions: Machine-learning prediction of early recurrence after ICC resection may inform tailored counseling, treatment, and recommendations. An easy-to-use calculator based on the RF model was developed and made available online., (© 2023. Society of Surgical Oncology.)

Background: The prognostic impact of major postoperative complications (POCs) for intrahepatic cholangiocarcinoma (ICC) remains ill-defined. We sought to analyze the relationship between POCs and outcomes relative to lymph node metastases (LNM) and tumor burden score (TBS)., Methods: Patients who underwent resection of ICC between 1990-2020 were included from an international database. POCs were defined according to Clavien-Dindo classification ≥ 3. The prognostic impact of POCs was estimated relative to TBS categories (i.e., high and low) and lymph node status (i.e., N0 or N1)., Results: Among 553 patients who underwent curative-intent resection for ICC, 128 (23.1%) individuals experienced POCs. Low TBS/N0 patients who experienced POCs presented with a higher risk of recurrence and death (3-year cumulative recurrence rate; POCs: 74.8% vs. no POCs: 43.5%, p = 0.006; 5-year overall survival [OS], POCs 37.8% vs. no POCs 65.8%, p = 0.003), while POCs were not associated with worse outcomes among high TBS and/or N1 patients. The Cox regression analysis confirmed that POCs were significant predictors of poor outcomes in low TBS/N0 patients (OS, hazard ratio [HR] 2.91, 95%CI 1.45-5.82, p = 0.003; recurrence free survival [RFS], HR 2.42, 95%CI 1.28-4.56, p = 0.007). Among low TBS/N0 patients, POCs were associated with early recurrence (within 2 years) (Odds ratio [OR] 2.79 95%CI 1.13-6.93, p = 0.03) and extrahepatic recurrence (OR 3.13, 95%CI 1.14-8.54, p = 0.03), in contrast to patients with high TBS and/or nodal disease., Conclusions: POCs were independent, negative prognostic determinants for both OS and RFS among low TBS/N0 patients. Perioperative strategies that minimize the risk of POCs are critical to improving prognosis, especially among patients harboring favorable clinicopathologic features., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Intrahepatic cholangiocarcinoma (ICC) is associated with poor long-term outcomes, and limited evidence exists on optimal resection margin width. This study used artificial intelligence to investigate long-term outcomes and optimal margin width in hepatectomy for ICC., Methods: The study enrolled patients who underwent curative-intent resection for ICC between 1990 and 2020. The optimal survival tree (OST) was used to investigate overall (OS) and recurrence-free survival (RFS). An optimal policy tree (OPT) assigned treatment recommendations based on random forest (RF) counterfactual survival probabilities associated with each possible margin width between 0 and 20 mm., Results: Among 600 patients, the median resection margin was 4 mm (interquartile range [IQR], 2-10). Overall, 379 (63.2 %) patients experienced recurrence with a 5-year RFS of 28.3 % and a 5-year OS of 38.7 %. The OST identified five subgroups of patients with different OS rates based on tumor size, a carbohydrate antigen 19-9 [CA19-9] level higher than 200 U/mL, nodal status, margin width, and age (area under the curve [AUC]: training, 0.81; testing, 0.69). The patients with tumors smaller than 4.8 cm and a margin width of 2.5 mm or greater had a relative increase in 5-year OS of 37 % compared with the entire cohort. The OST for RFS estimated a 46 % improvement in the 5-year RFS for the patients younger than 60 years who had small (<4.8 cm) well- or moderately differentiated tumors without microvascular invasion. The OPT suggested five optimal margin widths to maximize the 5-year OS for the subgroups of patients based on age, tumor size, extent of hepatectomy, and CA19-9 levels., Conclusions: Artificial intelligence OST identified subgroups within ICC relative to long-term outcomes. Although tumor biology dictated prognosis, the OPT suggested that different margin widths based on patient and disease characteristics may optimize ICC long-term survival., (© 2023. Society of Surgical Oncology.)

Background: The therapeutic role of lymphadenectomy (LND) for intrahepatic cholangiocarcinoma (ICC) patients remains ill-defined. We sought to analyze the therapeutic value of LND relative to tumor location and preoperative lymph node metastasis (LNM) risk., Methods: Patients who underwent curative-intent hepatic resection of ICC between 1990 and 2020 were included from a multi-institutional database. Therapeutic LND (tLND) was defined as LND that harvested ≥3 lymph nodes., Results: Among 662 patients, 178 (26.9%) individuals received tLND. Patients were categorized into central type ICC (n = 156, 23.6%) and peripheral type ICC (n = 506, 76.4%). Central type harbored multiple adverse clinicopathologic factors and worse overall survival (OS) compared with peripheral type (5-year OS, central: 27.0% vs. peripheral: 47.2%, p < 0.001). After consideration of preoperative LNM risk, patients with central type and high-risk LNM who underwent tLND survived longer than individuals who did not (5-year OS, tLND: 27.9% vs. non-tLND: 9.0%, p = 0.001), whereas tLND was not associated with better survival among patients with peripheral type ICC or low-risk LNM. The therapeutic index of hepatoduodenal ligament (HDL) and other regions was higher in central type than in peripheral type, which was more pronounced among high-risk LNM patients., Conclusions: Central type ICC with high-risk LNM should undergo LND involving regions beyond the HDL., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status., Method: Patients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status., Results: Among 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2-8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin (n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1-3 mm 38.5% vs. 3-10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1-3 mm 22.8% vs. 3-10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35-3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58-3.11, p = 0.50)., Conclusion: R0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology., (© 2022. Society of Surgical Oncology.)

Background: The interplay of carbohydrate antigen 19-9 (CA19-9) and tumor burden score (TBS) within intrahepatic cholangiocarcinoma remains ill-defined. We evaluated the roles of TBS and CA19-9 relative to overall survival (OS) and recurrence, as well as the predictive ability of the combined TBS and CA19-9 (CTC) grading system., Study Design: Patients undergoing liver resection for intrahepatic cholangiocarcinoma between 2000 and 2020 were identified using a multi-institutional database. The impact of CA19-9 and TBS on 5-year OS and 3-year recurrence was assessed, along with the prognostic accuracy of the CTC grading system (ie the composite score of CA19-9 level and TBS)., Results: Among 831 patients, the median age was 58.2 years and 482 (58.0%) were male. The median [IQR] CA19-9 level was 49.7 [17.0, 221.0] U/mL and TBS was 6.1 [4.1, 8.3]. Median [IQR] and 5-year OS were 36.9 [32.3, 43.1] months and 38.9%, respectively; 3-year recurrence was 68.9%. Five-year survival varied relative to CA19-9 (low vs high, 49.0% vs 19.7%) and TBS (low vs high, 53.6% vs 26.9%) (p < 0.001 for both). On multivariable analysis, high CA19-9 (hazard ratio [HR] 2.02, 95% CI 1.64 to 2.49) and high TBS (HR 1.64, 95% CI 1.32 to 2.06) remained independently associated with OS. In turn, the CTC grading score stratified 5-year OS (low vs intermediate vs high CTC, 57.7% vs 39.9% vs 12.6%; p < 0.001) and remained an independent prognostic factor (referent, low CTC; [intermediate CTC] HR 1.54, 95% CI 1.18 to 2.01; [high CTC] HR 3.28, 95% CI 2.47 to 4.36)., Conclusions: The interplay between tumor morphology and biology dictates long-term prognosis after liver resection for intrahepatic cholangiocarcinoma. Prognostic models such as the CTC grading system may inform discussions around prognosis, as well as help identify which patients with ICC may benefit more from neoadjuvant chemotherapy rather than up-front surgery., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: The prognostic role of tumor burden score (TBS) relative to albumin-bilirubin (ALBI) grade among patients undergoing curative-intent resection of ICC has not been examined., Methods: We identified patients who underwent curative-intent resection for ICC between 1990 and 2017 from a multi-institutional database. Multivariable analysis was performed to assess the effect of TBS relative to ALBI grade on both short- and long-term outcomes., Results: Among 724 patients, 360 (49.7%) patients had low TBS and low ALBI grade, 142 (19.6%) patients had low TBS and high ALBI grade, 138 (19.1%) patients had high TBS and low ALBI grade, and 84 patients (11.6%) had high TBS and high ALBI grade. Decreased tumor burden was associated with better long-term outcomes among patients with both low (5-year OS; low TBS vs. high TBS: 52.4% vs 21.4%; p < 0.001) and high ALBI grade (5-year OS; low TBS vs. high TBS: 40.7% vs 12.0%; p < 0.001). On multivariable analysis, higher ALBI grade was associated with greater odds of an extended hospital LOS (> 10 days) (OR 2.80, 95%CI 1.62-4.82; p < 0.001), perioperative transfusion (OR 2.04, 95%CI 1.25-3.36; p = 0.005), 90-day mortality (OR 2.56, 95%CI 1.12-5.81; p = 0.025), as well as a major complication (OR 1.99, 95%CI 1.13-3.49; p = 0.016) among patients with similar tumor burden. Of note, patients with high TBS and high ALBI grade had markedly worse overall survival compared with patients who had low TBS and low ALBI grade disease (HR 2.27; 95%CI 1.44-3.59; p < 0.001). Importantly, high TBS and high ALBI grade were strongly associated with both early recurrence (88.1%%) and 5-year risk of death (96.4%)., Conclusion: Both TBS (i.e., tumor morphology) and ALBI grade (i.e., hepatic function reserve) were strong predictors of outcomes among patients undergoing ICC resection. There was an interplay between TBS and ALBI grade relative to patient prognosis after hepatic resection of ICC with high ALBI grade predicting worse outcomes among ICC patients with different TBS., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: We sought to investigate whether the unique lateral patterns of lymphatic drainage impacted lymphadenectomy (LND), lymph node metastasis (LNM), and long-term survival of patients after curative hemi-hepatectomy for left- versus right-sided intrahepatic cholangiocarcinoma (ICC)., Methods: Data on patients who underwent curative hemi-hepatectomy for left- or right-sided ICC were collected from 15 high-volume centers worldwide, as well as from the Surveillance, Epidemiology, and End Results (SEER) registry. Primary outcomes included overall survival (OS) and disease-free survival (DFS)., Results: Among 697 patients identified from the multi-institutional database, patients who underwent hemi-hepatectomy for left-sided ICC (n = 363, 52.1%) were more likely to have an increased number of LND versus patients with right-sided ICC (n = 334, 47.9%) (median, left 5 versus right 3, p = 0.012), although the frequency (left 66.4% versus right 63.8%, p = 0.469) and station (beyond station no. 12, left 25.3% versus right 21.1%, p = 0.293) were similar. Consequently, left-sided ICC was associated with higher incidence of LNM (left 33.3% versus right 25.7%, p = 0.036), whereas the station and number of LNM were not different (both p > 0.1). There was no difference in OS (median, left 34.9 versus right 29.6 months, p = 0.130) or DFS (median, left 14.5 versus right 15.2 months, p = 0.771) among patients who underwent hemi-hepatectomy for left- versus right-sided ICC, which were also verified in the SEER dataset. LNM beyond station no. 12 was associated with even worse long-term survival versus LNM within station no. 12 among patients with either left- or right-sided ICC after curative-intent resection (all p < 0.05)., Conclusions: The unique lateral patterns of lymphatic drainage were closely related to utilization of LND, as well as LNM of left- versus right-sided ICC., (© 2022. Society of Surgical Oncology.)

Introduction: While generally associated with poor prognosis, intrahepatic cholangiocarcinoma (ICC) can have a heterogeneous presentation and natural history. We sought to identify specific ICC subtypes that may be associated with varied long-term outcomes and patterns of recurrence after liver resection., Methods: Patients who underwent curative-intent resection for ICC from 2000 to 2020 were identified from a multi-institutional database. Hierarchical cluster analysis characterized three ICC subtypes based on morphology (i.e., tumor burden score [TBS]) and biology (i.e., preoperative neutrophil-to-lymphocyte ratio [NLR] and CA19-9 levels)., Results: Among 598 patients, the cluster analysis identified three ICC subtypes: Common (n = 300, 50.2%) (median, TBS: 4.5; NLR: 2.4; CA19-9: 38.0 U/mL); Proliferative (n = 246, 41.1%) (median, TBS: 8.8; NLR: 2.9; CA19-9: 71.2 U/mL); Inflammatory (n = 52, 8.7%) (median, TBS: 5.4; NLR: 12.6; CA19-9: 26.7 U/mL). Median overall survival (OS) (Common: 72.0 months; Proliferative: 31.4 months; Inflammatory: 22.9 months) and recurrence-free survival (RFS) (Common: 21.5 months; Proliferative: 11.9 months; Inflammatory: 9.0 months) varied considerably among the different ICC subtypes (all p < 0.001). Even though patients with Inflammatory ICC had more favorable T-(T1/T2, Common: 84.4%; Proliferative: 80.6%; Inflammatory: 86.5%) and N-(N0, Common: 14.0%; Proliferative: 20.7%; Inflammatory: 26.9%) disease, the Inflammatory subtype was associated with a higher incidence of intra- and extrahepatic recurrence (Common: 15.8%; Proliferative: 24.2%; Inflammatory: 28.6%) (all p = 0.01)., Conclusions: Cluster analysis identified three distinct subtypes of ICC based on TBS, NLR, and CA19-9. ICC subtype was associated with RFS and OS and predicted worse outcomes among patients. Despite more favorable T- and N-disease, the Inflammatory ICC subtype was associated with worse outcomes ICC subtype should be considered in the prognostic stratification of patients., (© 2022. Society of Surgical Oncology.)

Purpose: To investigate recurrence patterns after surgery for intrahepatic cholangiocarcinoma (ICC) relative to lymph node status, tumor extension, tumor burden score (TBS), and adjuvant chemotherapy., Methods: Patients who underwent curative-intent resection for ICC from 1990 to 2020 were enrolled from a multi-institutional database. The hazard function was applied to plot the hazard rates over time, with further stratification by T and N AJCC 8th edition categories, TBS, and adjuvant chemotherapy., Results: A total of 1192 patients underwent curative-intent resection for ICC and 59.9% experienced recurrence. Overall, the peak of recurrence occurred at 6.6 months. Among patients with negative lymph nodes, the T4-category had a higher peak rate of recurrence (0.1199 at 10.2 months) compared with other T-categories, while high TBS had an earlier peak of recurrence (4.2 months) compared with lower TBS. Among patients with N1 disease, T2-T4 categories had multipeak patterns of recurrence with higher hazard rates during the first 3 years after surgery in comparison with T1-category, while patients with high TBS had an earlier (4.0 months) and higher hazard peak rate compared with lower TBS groups. The administration of adjuvant chemotherapy was associated with delayed hazard rates of recurrence for N1 (4 months) and NX (6 months) categories., Discussion: The novel application of the hazard function to assess hazard rates and timing patterns of recurrence following resection for ICC demonstrated that recurrence varied based on T- and N-categories, as well as TBS. Hazard function-based recurrence data may be helpful to tailor counseling, surveillance, and adjuvant therapy recommendations., (© 2022. Society of Surgical Oncology.)

Background: The aim of this study was to develop a predictive model to identify individuals most likely to derive overall survival (OS) benefit from adjuvant chemotherapy (AC) after hepatic resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent hepatic resection of ICC between 1990 and 2020 were identified from a multi-institutional database. Factors associated with worse OS were identified and incorporated into an online predictive model to identify patients most likely to benefit from AC., Results: Among 726 patients, 189 (26.0%) individuals received AC. Factors associated with OS on multivariable analysis included CA19-9 (Hazard Ratio [HR]1.17, 95%CI 1.04-1.31), tumor burden score (HR1.09, 95%CI 1.04-1.15), T-category (T2/3/4, HR1.73, 95%CI 1.73-2.64), nodal disease (N1, HR3.80, 95%CI 2.02-7.15), tumor grade (HR1.88, 95%CI 1.00-3.55), and morphological subtype (HR2.19, 95%CI 1.08-4.46). A weighted predictive score was devised and made available online (https://yutaka-endo.shinyapps.io/ICCrisk&#95;model&#95;for&#95;AC/). Receipt of AC was associated with a survival benefit among patients at high/medium-risk (high: no AC, 0% vs. AC, 20.6%; medium: no AC, 36.4% vs. 40.8%; both p < 0.05) but not low-risk (low: no AC, 65.1% vs. AC, 65.1%; p = 0.73) tumors., Conclusion: An online predictive model based on tumor characteristics may help identify which patients may benefit the most from AC following resection of ICC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

The study was designed to discuss the effect of stratification factors in the Mayo staging on the prognosis of hilar cholangiocarcinoma (HCCA) patients, and to evaluate the predictive value of the Mayo staging on the prognosis. The Kaplan-Meier survival curve and Log-rank test were used to perform univariate analysis on each index and obtain statistically significant influencing factors. The Kaplan-Meier survival curve and Log-rank test were used to analyze the correlation between the two staging systems and the survival period. The receiver operating characteristic (ROC) curves were used for each single staging system trend analysis, and comparison of their curve area to determine prognosis prediction ability for patients with HCCA. According to Kaplan-Meier survival curve changes and Log-rank test results, it was found that both staging systems were correlated with the survival time of the patients (P < .001). Through a pairwise comparison within the stages, it was found that the heterogeneity between the stages within the Mayo staging is very good, which was better than the TNM staging. A single trend analysis of the prognostic assessment capabilities of the two systems found that the area under the ROC curve of Mayo staging system (AUC = 0.587) was the largest and better than the TNM staging system (AUC = 0.501). Mayo staging can be used for preoperative patient prognosis assessment which can provide better stratification ability based on a single-center small sample study, and the predictive value is better than TNM staging., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The current study aimed to develop a dynamic prognostic model for patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) using landmark analysis., Methods: Patients who underwent curative-intent surgery for ICC from 1999 to 2017 were selected from a multi-institutional international database. A landmark analysis to undertake dynamic overall survival (OS) prediction was performed. A multivariate Cox proportional hazard model was applied to measure the interaction of selected variables with time. The performance of the model was internally cross-validated via bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index. Accuracy was evaluated with calibration plots., Results: Variables retained in the multivariable Cox regression OS model included age, tumor size, margin status, morphologic type, histologic grade, T and N category, and tumor recurrence. The effect of several variables on OS changed over time. Results were provided as a survival plot and the predicted probability of OS at the desired time in the future. For example, a 65-year-old patient with an intraductal, T1, grade 3 or 4 ICC measuring 3 cm who underwent an R0 resection had a calculated estimated 3-year OS of 76%. The OS estimate increased if the patient had already survived 1 year (79%). The discrimination ability of the final model was very good (C-index: 0.80)., Conclusion: The long-term outcome for patients undergoing curative-intent surgery for ICC should be adjusted based on follow-up time and intervening events. The model in this study showed excellent discriminative ability and performed well in the validation process., (© 2022. Society of Surgical Oncology.)

Background: Lymph node (LN) metastasis is significantly associated with worse prognosis for patients with intrahepatic cholangiocarcinoma (ICC). Improvement in preoperative assessment on LN metastasis helps in treatment decision-making. We aimed to investigate the role of radiomics-based method in predicting LN metastasis for patients with ICC., Methods: A total of 296 patients with ICC who underwent curative-intent hepatectomy and lymphadenectomy at two centers in China were analyzed. Radiomic features, including histogram- and wavelet-based features, shape and size features, and texture features were extracted from four-phase computerized tomography (CT) images. The clinical and conventional radiological variables which were independently associated with LN metastasis were also identified. A combined nomogram predicting LN metastasis was developed, and its performance was determined by discrimination, calibration, and stratification of long-term prognosis. The results were validated by the internal and external validation cohorts., Results: Twenty-four radiomic features were selected into the nomogram. The established nomogram demonstrated good discrimination and calibration, with areas under the curve (AUCs) of 0.98 [95% confidence interval (CI) 0.96-0.99], 0.93 (0.88-0.98), and 0.89 (0.81-0.96) in the training and two validation cohorts, respectively. The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of patients with high risk of LN metastasis as grouped by nomogram were poorer than those of patients with low risk in the training cohort (OS 28.8% versus 53.9%, p < 0.001; RFS 26.3% versus 44.2%, p = 0.001). Similar results were observed in the two validation cohorts., Conclusions: Radiomics-based method provided accurate prediction of LN metastasis and prognostic assessment for ICC patients, and might aid the preoperative surgical decision., (© 2022. Society of Surgical Oncology.)

Importance: Intrahepatic cholangiocarcinoma (iCCA) is often multifocal (ie, satellites or intrahepatic metastases) at presentation., Objective: To compare the overall survival (OS) of patients with multifocal iCCA after hepatic arterial infusion pump (HAIP) floxuridine chemotherapy vs resection., Design, Setting, and Participants: In this cohort study, patients with histologically confirmed, multifocal iCCA were eligible. The HAIP group consisted of consecutive patients from a single center who underwent HAIP floxuridine chemotherapy for unresectable multifocal iCCA between January 1, 2001, and December 31, 2018. The resection group consisted of consecutive patients from 12 centers who underwent a curative-intent resection for multifocal iCCA between January 1, 1990, and December 31, 2017. Resectable metastatic disease to regional lymph nodes and previous systemic therapy were permitted. Patients with distant metastatic disease (ie, stage IV), those who underwent resection before starting HAIP floxuridine chemotherapy, and those who received a liver transplant were excluded. Data were analyzed on September 1, 2021., Main Outcomes and Measures: Overall survival in the 2 treatment groups was compared using the Kaplan-Meier method and log-rank test., Results: A total of 319 patients with multifocal iCCA were included: 141 in the HAIP group (median [IQR] age, 62 [53-70] years; 79 [56.0%] women) and 178 in the resection group (median [IQR] age, 60 [50-69] years; 91 [51.1%] men). The HAIP group was characterized by a higher percentage of bilobar disease (88.0% [n = 124] vs 34.3% [n = 61]), larger tumors (median, 8.4 cm vs 7.0 cm), and a higher proportion of patients with 4 or more lesions (66.7% [94] vs 24.2% [43]). Postoperative mortality after 30 days was 0.8% (95% CI, 0.0%-2.1%) in the HAIP group vs 6.2% (95% CI, 2.3%-9.7%) in the resection group (P = .01). The median OS for HAIP was 20.3 months vs 18.9 months for resection (P = .32). Five-year OS in patients with 2 or 3 lesions was 23.7% (95% CI, 12.3%-45.7%) in the HAIP group vs 25.7% (95% CI, 17.9%-37.0%) in the resection group. Five-year OS in patients with 4 or more lesions was 5.0% (95% CI, 1.7%-14.3%) in the HAIP group vs 6.8% (95% CI, 1.8%-25.3%) in the resection group. After adjustment for tumor diameter, number of tumors, and lymph node metastases, the hazard ratio of HAIP vs resection was 0.75 (95% CI, 0.55-1.03; P = .07)., Conclusions and Relevance: This cohort study found that patients with multifocal iCCA had similar OS after HAIP floxuridine chemotherapy vs resection. Resection of multifocal intrahepatic cholangiocarcinoma needs to be considered carefully given the complication rate of major liver resection; HAIP floxuridine chemotherapy may be an effective alternative option.

Background: The aim of this study was to investigate the prognostic impact of perineural invasion (PNI) on tumour recurrence and survival among patients with resected intrahepatic cholangiocarcinoma (ICC)., Methods: This was a multicentre, retrospective study of patients who underwent resection with curative intent for ICC between 2000 and 2017. The relationship between PNI, clinicopathological characteristics, and long-term survival was analysed in the overall cohort and the subset of patients with early-stage ICC., Results: Among 1095 patients who underwent resection of ICC, PNI was present in 239 (21.8 per cent). In univariable analysis, PNI was associated with worse disease-free survival (DFS) (median 13.2 versus 16.1 months for patients with and without PNI respectively; P = 0.038) and overall survival (OS) (26.4 versus 41.5 months; P < 0.001). In multivariable analysis, PNI was an independent risk factor associated with reduced DFS (hazard ratio (HR) 1.56, 95 per cent c.i. 1.06 to 2.13; P = 0.019) and OS (HR 1.74, 1.16 to 2.60; P = 0.007). In subgroup analysis of patients with early-stage disease (AJCC T1-2, 981 patients; or N0, 249 patients), PNI remained associated with worse DFS (T1-2: median 13.7 versus 16.6 months in patients with and without PNI respectively, P = 0.019; N0: 11.7 versus 17.5 months, P = 0.022) and OS (T1-2: 28.5 versus 45.7 months, P < 0.001; N0: 34.9 versus 47.5 months, P = 0.036)., Conclusion: PNI is a strong independent predictor of tumour recurrence and long-term survival following resection of ICC with curative intent, even among patients with early-stage disease. The presence of PNI should be assessed routinely., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To determine the prognostic implication of the number and station of LNM, and the minimal number of LNs needed for evaluation to accurately stage patients with intrahepatic cholangiocarcinoma (ICC)., Background: Impact of the number and station of LNM on long-term survival, and the minimal number of LNs needed for accurate staging of ICC patients remain poorly defined., Methods: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide. External validation was performed using the SEER registry. Primary outcomes included overall (OS), disease-specific, and recurrence-free survival., Results: Among 603 patients who underwent curative-intent resection, median and 5-year OS were 30.6 months and 30.4%. Patients with 1 or 2 LNM had comparable worse OS versus patients with no nodal disease (median OS, 1 LNM 18.0, 2 LNM 20.0 vs no LNM 45.0 months, both P < 0.001), yet better OS versus patients with 3 or more LNM (median OS, 1-2 LNM 19.8 vs ≥3 LNM 16.0 months, P < 0.01). On multivariable analysis, a proposed new nodal staging with N1 (1-2 LNM) (Ref. N0, HR 2.40, P < 0.001) and N2 (≥3 LNM) [Ref. N0, hazard ratio (HR) 3.85, P < 0.001] categories were independently associated with incrementally worse OS. Patients with no nodal metastasis, 1-2 LNM and ≥3 LNM also had an increasingly worse disease-specific survival, and recurrence-free survival (both P < 0.05). Total number of LNs examined ≥6 had the greatest discriminatory power relative to OS among patients with 1-2 LNM, and patients with ≥3 LNM in both the multi-institutional (area under the curve 0.780) and SEER database (area under the curve 0.820) (n = 1036). Among patients who underwent an adequate regional lymphadenectomy (total number of LNs examined ≥6), LNM beyond the HDL was associated with worse OS versus LNM within the HDL only (median OS, 14.0 vs 24.0 months, HR 2.41, P = 0.003)., Conclusion: Standard lymphadenectomy of at least 6 LNs is strongly recommended and should include examination beyond station 12 to have the greatest chance of accurate staging. The proposed new nodal staging of N0, N1, and N2 should be considered to stratify outcomes among patients after curative-intent resection of ICC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To improve the prognostic accuracy of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC) with establishment and validation of a modified TNM (mTNM) staging system., Methods: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide (n = 643). An external validation dataset was obtained from the SEER registry (n = 797). The mTNM staging system was proposed by redefining T categories, and incorporating the recently proposed N status as N0 (no lymph node metastasis [LNM]), N1 (1-2 LNM) and N2 (≥3 LNM)., Results: The 8th AJCC TNM staging system failed to stratify overall survival (OS) of stage II versus IIIA, stage IIIB versus IV, as well as overall stage III versus IV among all patients from the two databases, as well as stage I versus II, and stage III versus III among patients who had ≥6 LNs examined. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the multi-institutional (Median OS, stage I 69.8 vs. II 37.1 vs. III 18.9 vs. IV 16.4 months, all p < 0.05), and SEER (Median OS, stage I 87.0 vs. II 29.3 vs. III 17.7 vs. IV 14.2 months, all p < 0.05) datasets, which was also verified among patients who had ≥6 lymph node harvested from both databases., Conclusion: The modified TNM staging system for ICC using the new T and N definitions provided an improved means to stratify patients relative to long-term OS versus the 8th AJCC staging., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Hepatolithiasis is associated with the development of intrahepatic cholangiocarcinoma (ICC). This study sought to investigate risk factors of ICC for hepatolithiasis after partial hepatectomy (PH) and to develop a model for predicting ICC risk., Methods: Data on consecutive patients who underwent PH for hepatolithiasis at the Eastern Hepatobiliary Surgery Hospital between January 2009 and December 2011 were reviewed. Independent risk factors of ICC identified by Cox regression model were used to develop a nomogram in predicting ICC after PH for hepatolithiasis., Results: Of 2056 patients, 168 developed ICC at a median follow-up of 7.2 years. The cumulative incidences of ICC at 3, 5, and 8 years after PH for hepatolithiasis were 3.0%, 6.5%, and 12.9%, respectively. Independent risk factors of ICC were identified to be a long duration of hepatolithiasis-related symptoms (hazard ratio, 1.088 [95% confidence interval, 1.057-1.120]), metabolic syndrome (2.036 [1.210-3.425]), a high neutrophil-to-lymphocyte ratio (1.250 [1.009-2.816] for 3-5 vs ≤3; 1.538 [1.048-2.069] for ≥5 vs ≤3), hepatic atrophy (1.711 [1.189-2.462]), segmental intensity differences (1.513 [1.052-2.176]), persistent biliary strictures (2.825 [1.480-5.391]), and residual stone disease (2.293 [1.511-3.481]). By incorporating these factors, a constructed nomogram showed a concordance index of 0.721 to predict ICC. The calibration plots demonstrated good agreement between observed and predicted morbidities. The optimal cutoff point for the nomogram was 48 in differentiating between high and low-risk of ICC., Conclusions: A nomogram for predicting ICC after PH for hepatolithiasis was constructed based on risk factors of developing ICC. Patients with a nomogram point of ≥48 were predicted to have a high risk of ICC., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: The objective of the current study was to develop a model to predict the likelihood of occult lymph node metastasis (LNM) prior to resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent hepatectomy for ICC between 2000 and 2017 were identified using a multi-institutional database. A novel model incorporating clinical and preoperative imaging data was developed to predict LNM., Results: Among 980 patients who underwent resection of ICC, 190 (19.4%) individuals had at least one LNM identified on final pathology. An enhanced imaging model incorporating clinical and imaging data was developed to predict LNM ( https://k-sahara.shinyapps.io/ICC&#95;imaging/ ). The performance of the enhanced imaging model was very good in the training data set (c-index 0.702), as well as the validation data set with bootstrapping resamples (c-index 0.701) and outperformed the preoperative imaging alone (c-index 0.660). The novel model predicted both 5-year overall survival (OS) (low risk 48.4% vs. high risk 18.4%) and 5-year disease-specific survival (DSS) (low risk 51.9% vs. high risk 25.2%, both p < 0.001). When applied among Nx patients, 5-year OS and DSS of low-risk Nx patients was comparable with that of N0 patients, while high-risk Nx patients had similar outcomes to N1 patients (p > 0.05)., Conclusion: This tool may represent an opportunity to stratify prognosis of Nx patients and can help inform clinical decision-making prior to resection of ICC.

Introduction: While tumor burden (TB) has been associated with outcomes among patients with hepatocellular carcinoma, the role of overall TB in intrahepatic cholangiocarcinoma (ICC) remains poorly defined., Methods: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified from a multi-institutional database. The impact of TB on overall (OS) and disease-free survival (DFS) was evaluated in the multi-institutional database and validated externally., Results: Among 1101 patients who underwent curative-intent resection of ICC, 624 (56.7%) had low TB, 346 (31.4%) medium TB, and 131 (11.9%) high TB. OS incrementally worsened with higher TB (5-year OS; low TB: 48.3% vs medium TB: 29.8% vs high TB: 17.3%, p < 0.001). Similarly, patients with low TB had better DFS compared with medium and high TB patients (5-year DFS: 38.3% vs 18.7% vs 6.9%, p < 0.001). On multivariable analysis, TB was independently associated with OS (medium TB: HR = 1.40, 95% CI 1.14-1.71; high TB: HR = 1.89, 95% CI 1.46-2.45) and DFS (medium TB, HR = 1.61, 95% CI 1.33-1.96; high TB: HR = 2.03, 95% CI 1.56-2.64). Survival analysis revealed an excellent prognostic discrimination using the TB among the external validation cohort (3-year OS; low TB: 44.8%, medium TB: 29.3%; high TB: 23.3%, p = 0.03; 3-year DFS: low TB: 32.7%, medium TB: 10.7%; high TB: 0%, p < 0.001). While neoadjuvant chemotherapy was not associated with survival across the TB groups, receipt of adjuvant chemotherapy was associated with increased survival among patients with high TB (5-year OS: 24.4% vs 13.4%, p = 0.02)., Conclusion: Overall TB dictated prognosis among patients with resectable ICC. TB may be used as a tool to help guide post-resection treatment strategies.

Preoperative evaluation of hepatic functional reserve in patients with hilar cholangiocarcinoma (hCCA) has vital clinical significance for prevention of posthepatectomy liver failure (PHLF) and mortality. The aim of the present study was to evaluate the clinical significance of the indocyanine green retention rate at 15 minutes (ICG R15) and related factors of postoperative outcomes in patients with hCCA. 147 patients who scheduled for hCCA resection underwent a preoperative ICG test between May 2015 and May 2020 and were prospectively analyzed. Single-factor analysis was used to evaluate the risk factors for PHLF and postoperative outcomes in hCCA. After univariate analysis, significant differences in ICG R15 were found between the PHLF group and the liver function recovered well (LFRW) group ( P ≤ 0.05). In terms of postoperative complications, ICG R15 was also a risk factor for moderate-to-severe postoperative complications. Preoperative ICG R15 was significantly associated with PHLF and moderate-to-severe postoperative complications. ICG R15 may become an ideal clinical indicator for the evaluation of liver function reserve before hCCA and can better predict the postoperative complications., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Min Li et al.)

Introduction: Patients with intrahepatic cholangiocarcinoma (ICC) generally have a poor prognosis, yet there can be heterogeneity in the patterns of presentation and associated outcomes. We sought to identify clusters of ICC patients based on preoperative characteristics that may have distinct outcomes based on differing patterns of presentation., Methods: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified using a multi-institutional database. A cluster analysis was performed based on preoperative variables to identify distinct patterns of presentation. A classification tree was built to prospectively assign patients into cluster assignments., Results: Among 826 patients with ICC, three distinct presentation patterns were noted. Specifically, Cluster 1 (common ICC, 58.9%) consisted of individuals who had a small-size ICC (median 4.6 cm) and median carbohydrate antigen (CA) 19-9 and neutrophil-to-lymphocyte ratio (NLR) levels of 40.3 UI/mL and 2.6, respectively; Cluster 2 (proliferative ICC, 34.9%) consisted of patients who had larger-size tumors (median 9.0 cm), higher CA19-9 levels (median 72.0 UI/mL), and similar NLR (median 2.7); Cluster 3 (inflammatory ICC, 6.2%) comprised of patients with a medium-size ICC (median 6.2 cm), the lowest range of CA19-9 (median 26.2 UI/mL), yet the highest NLR (median 13.5) (all p < 0.05). Median OS worsened incrementally among the three different clusters {Cluster 1 vs. 2 vs. 3; 60.4 months (95% confidence interval [CI] 43.0-77.8) vs. 27.2 months (95% CI 19.9-34.4) vs. 13.3 months (95% CI 7.2-19.3); p < 0.001}. The classification tree used to assign patients into different clusters had an excellent agreement with actual cluster assignment (κ = 0.93, 95% CI 0.90-0.96)., Conclusion: Machine learning analysis identified three distinct prognostic clusters based solely on preoperative characteristics among patients with ICC. Characterizing preoperative patient heterogeneity with machine learning tools can help physicians with preoperative selection and risk stratification of patients with ICC.

Background: The objective of this study was to examine whether the systemic immune inflammation index (SII) was associated with prognosis among patients following resection of intrahepatic cholangiocarcinoma (ICC)., Methods: The impact of SII on overall (OS) and cancer-specific survival (CSS) following resection of ICC was assessed. The performance of the final multivariable models that incorporated inflammatory markers (i.e. neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR] and SII [platelets∗NLR]) was assessed using the Harrell's concordance index., Results: Patients with high SII had worse 5-year OS (37.7% vs 46.6%, p < 0.001) and CSS (46.1% vs 50.1%, p < 0.001) compared with patients with low SII. An elevated SII (HR = 1.70, 95% CI 1.23-2.34) and NLR (HR = 1.58, 95% CI 1.10-2.27) independently predicted worse OS, whereas high PLR (HR = 1.17, 95% CI 0.85-1.60) was no longer associated with prognosis. Only SII remained an independent predictor of CSS (HR = 1.55, 95% CI 1.09-2.21). The SII multivariable model outperformed models that incorporated PLR and NLR relative to OS (c-index; 0.696 vs 0.689 vs 0.692) and CSS (c-index; 0.697 vs 0.689 vs 0.690)., Conclusion: SII independently predicted OS and CSS among patients with resectable ICC. SII may be a better predictor of outcomes compared with other markers of inflammatory response among patients with resectable ICC., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: To assess conditional survival (CS) according to recurrence status, as well as conditional disease-free survival (cDFS) among patients with intrahepatic cholangiocarcinoma (ICC)., Methods: CS and cDFS were evaluated among ICC patients who underwent curative-intent resection for ICC by using a multi-institutional database. Five-year CS (CS5) at "x" years was calculated separately for patients who did and did not experience recurrence. The cDFS3 at "x" years was defined as the chance to be disease-free for an additional 3 years after not having experienced a recurrence for "x" years postoperatively., Results: Among 1221 patients, median OS was 36.8 months. While estimated actuarial OS decreased over time, CS5 increased as patients survived over longer periods of time and reached 93.9% at 4 years among 139 patients who did not experience a recurrence. Among the 725 (59.4%) patients who did experience a tumor recurrence, CS5 decreased to 17.7% the first postoperative year; however, CS5 subsequently increased to 79.7% for 81 patients who had survived 4 years after surgery. While actuarial DFS decreased from 54.6% at 1 year to 28.2% at 5 years, estimated cDFS3 following liver resection increased over time. Of note, patients with known risk factors for recurrence had even more marked improvements in cDFS3 over subsequent years versus patients without risk factors for recurrence., Conclusion: CS and cDFS changed over time according to the presence of disease-specific risk factors, as well as the presence of recurrence.

Long non-coding RNAs (lncRNAs) have extremely complex roles in the progression of intrahepatic cholangiocarcinoma (ICC) and remain to be elucidated. By cytological and animal model experiments, this study demonstrated that the expression of lncRNA MNX1-AS1 was remarkably elevated in ICC cell lines and tissues, and was highly and positively correlated with motor neuron and pancreas homeobox protein 1 (MNX1) expression. MNX1-AS1 significantly facilitated the proliferation, migration, invasion, and angiogenesis in ICC cells in vitro, and remarkably promoted tumor growth and metastasis in vivo. Further study revealed that MNX1-AS1 promoted the expression of MNX1 via recruiting transcription factors c-Myc and myc-associated zinc finger protein (MAZ). Furthermore, MNX1 upregulated the expression of Ajuba protein via binding to its promoter region, and subsequently, Ajuba protein suppressed the Hippo signaling pathway. Taken together, our results uncovered that MNX1-AS1 can facilitate ICC progression via MNX1-AS1/c-Myc and MAZ/MNX1/Ajuba/Hippo pathway, suggesting that MNX1-AS1 may be able to serve as a potential target for ICC treatment.

Importance: Although surgery offers the best chance of a potential cure for patients with localized, resectable intrahepatic cholangiocarcinoma (ICC), prognosis of patients remains dismal largely because of a high incidence of recurrence., Objective: To predict very early recurrence (VER) (ie, recurrence within 6 months after surgery) following resection for ICC in the pre- and postoperative setting., Design, Setting, and Participants: Patients who underwent curative-intent resection for ICC between May 1990 and July 2016 were identified from an international multi-institutional database. The study was conducted at The Ohio State University in collaboration with all other participating institutions. The data were analyzed in December 2019., Main Outcomes and Measures: Two logistic regression models were constructed to predict VER based on pre- and postoperative variables. The final models were used to develop an online calculator to predict VER and the tool was internally and externally validated., Results: Among 880 patients (median age, 59 years [interquartile range, 51-68 years]; 388 women [44.1%]; 428 [50.2%] white; 377 [44.3%] Asian; 27 [3.2%] black]), 196 (22.3%) developed VER. The 5-year overall survival among patients with and without VER was 8.9% vs 49.8%, respectively (P < .001). A preoperative model was able to stratify patients relative to the risk for VER: low risk (6-month recurrence-free survival [RFS], 87.7%), intermediate risk (6-month RFS, 72.3%), and high risk (6-month RFS, 49.5%) (log-rank P < .001). The postoperative model similarly identified discrete cohorts of patients based on probability for VER: low risk (6-month RFS, 90.0%), intermediate risk (6-month RFS, 73.1%), and high risk (6-month RFS, 48.5%) (log-rank, P < .001). The calibration and predictive accuracy of the pre- and postoperative models were good in the training (C index: preoperative, 0.710; postoperative, 0.722) as well as the internal (C index: preoperative, 0.715; postoperative, 0.728; bootstrapping resamples, n = 5000) and external (C index: postoperative, 0.672) validation data sets., Conclusion and Relevance: An easy-to-use online calculator was developed to help clinicians predict the chance of VER after curative-intent resection for ICC. The tool performed well on internal and external validation. This tool may help clinicians in the preoperative selection of patients for neoadjuvant therapy as well as during the postoperative period to inform surveillance strategies.

Background: The objective of the current study was to assess the impact of serum CA19-9 and CEA and their combination on survival among patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent curative-intent resection of ICC between 1990 and 2016 were identified using a multi-institutional database. Patients were categorized into four groups based on combinations of serum CA19-9 and CEA (low vs. high). Factors associated with 1-year mortality after hepatectomy were examined., Results: Among 588 patients, 5-year OS was considerably better among patients with low CA19-9/low CEA (54.5%) compared with low CA19-9/high CEA (14.6%), high CA19-9/low CEA (10.0%), or high CA19-9/high CEA (0%) (P < 0.001). No difference in 1-year OS existed between patients who had either high CA19-9 (high CA19-9/low CEA: 70.4%) or high CEA levels (low CA19-9/high CEA: 72.5%) (P = 0.92). Although patients with the most favorable tumor marker profile (low CA19-9/low CEA) had the best 1-year survival (87.9%), 15.1% (n = 39) still died within a year of surgery. Among patients with low CA19-9/low CEA, a high neutrophil-to-lymphocyte ratio (NLR) (odds ratio 1.09; 95% confidence interval 1.03-1.64) and large size tumor (odds ratio 3.34; 95% confidence interval 1.40-8.10) were associated with 1-year mortality (P < 0.05)., Conclusions: Patients with either a high CA19-9 and/or high CEA had poor 1-year survival. High NLR and large tumor size were associated with a greater risk of 1-year mortality among patients with favorable tumor marker profile.

Background: To compare outcomes of patients with arterially hyperenhancing intrahepatic cholangiocarcinomas (ICC) and arterially hypoenhancing ICCs after partial hepatectomy in a cohort with an analysis of prognostic factors., Methods: From June 2009 to October 2011, a prospective cohort of 68 patients with single resectable ICCs (≤5 cm in diameter) underwent gadolinium contrast-enhanced dynamic-phase magnetic resonance imaging and were treated with partial hepatectomy. Patients were divided into those with arterially hyperenhancing ICCs (n = 28) or arterially hypoenhancing ICCs (n = 40). Clinic-radiologic-pathologic results and survival of these patients were compared and statistically analyzed., Results: The median overall survival (OS) time was significantly longer in the arterially hyperenhancing ICCs (56.8 vs. 37.0 months) (p = 0.044). At pathologic evaluation, arterially hyperenhancing ICCs showed significantly higher microvessel count (MVC) than arterially hypoenhancing ICCs (106.2 ± 47.5 vs. 46.9 ± 21.6/mm 2 , p = 0.001). Arterial enhancement of ICCs was found to be an independent prognostic factor for longer survival., Conclusion: The presence of arterially hyperenhancing ICCs is related to higher MVC and exhibit a better OS time than arterially hypoenhancing ICCs after partial hepatectomy., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) are commonly used to treat intrahepatic recurrent liver cancers. However, there is no information regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma (ICC) after resection., Methods: A total of 275 patients with localized recurrent ICC who received either TACE (n = 183) or PMCT (n = 92) were studied. A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT. Prognostic factors for TACE and PMCT were identified respectively. Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values., Results: Both TACE and PMCT provided curativeness in partial patients (5-year overall survival: 21.4% and 6.1%, respectively), but TACE provided better survival benefit in both overall patients (hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.50-0.97; P = 0.034) and propensity score matching analysis (HR = 0.69; 95% CI: 0.47-0.98; P = 0.041). Independent prognostic factors for TACE were tumor size >5 cm, poor differentiation, and major resection, whereas poor differentiation, hepatitis B virus infection, cholelithiasis, and lymph node metastasis were identified for PMCT. Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70, respectively., Conclusions: TACE provided better survival benefits compared to PMCT. However, there was a disparity in prognostic factors, suggesting evaluation of the two nomograms may be supportive in modality selection. Further prospective validation studies are required for the results to be applied in clinical medicine., (Copyright © 2020 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Estimating prognosis in the preoperative setting is challenging, as most survival risk scores rely exclusively on postoperative factors. We sought to develop a composite score that incorporated preoperative liver, tumor, nutritional, and inflammatory markers to predict long-term outcomes after resection of intrahepatic cholangiocarcinoma (ICC)., Study Design: Patients who underwent curative-intent hepatectomy for ICC between 2000 and 2017 were identified using an international multi-institutional database. Clinicopathologic factors were assessed using bivariate and multivariable analysis and a prognostic model to estimate overall survival (OS) based only on preoperative laboratory values (LabScore) was developed and validated., Results: Among 660 patients, median OS was 43.2 months and 5-year OS rate was 42.4%. On multivariable analysis, laboratory values associated with OS included carbohydrate antigen 19-9 (hazard ratio [HR] 1.16; 95% CI 1.05 to 1.27), neutrophil-to-lymphocyte ratio (HR 1.09; 95% CI, 1.05 to 1.13), platelet count (HR 1.01; 95% CI, 1.00 to 1.01), and albumin (HR 0.75; 95% CI, 0.62 to 0.92). A weighted LabScore was constructed based on the formula: (8.2 + 1.45 × natural logarithm of carbohydrate antigen 19-9 + 0.84 × neutrophil-to-lymphocyte ratio + 0.03 × platelets - 2.83 × albumin). Patients with a LabScore of 0 to 9 (n = 223), 10 to 19 (n = 353) and ≥20 (n = 88) had incrementally worse 5-year OS rates of 54.9%, 38.2% and 21.6%, respectively (p < 0.001). The model demonstrated good performance in both the test (c-index 0.70) and validation cohorts (c-index 0.67), as well as outperformed individual laboratory markers, the prognostic nutritional index (c-index 0.58), and American Joint Committee on Cancer staging system (c-index 0.60)., Conclusions: A preoperative LabScore was able to predict long-term outcomes of patients after resection for ICC better than American Joint Committee on Cancer staging system. The LabScore can be used to preoperatively identify patients who will benefit the most from upfront operation or alternative treatment options, including neoadjuvant chemotherapy before resection., (Copyright © 2020 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Accurate risk stratification and patient selection is necessary to identify patients who will benefit the most from surgery or be better treated with other non-surgical treatment strategies. We sought to identify which patients in the preoperative setting would likely derive the most or least benefit from resection of intrahepatic cholangiocarcinoma (ICC)., Methods: Patients who underwent curative-intent resection for ICC between 1990 and 2017 were identified from an international multi-institutional database. A machine-based classification and regression tree (CART) was used to generate homogeneous groups of patients relative to overall survival (OS) based on preoperative factors., Results: Among 1146 patients, CART analysis revealed tumor number and size, albumin-bilirubin (ALBI) grade and preoperative lymph node (LN) status as the strongest prognostic factors associated with OS among patients undergoing resection for ICC. In turn, four groups of patients with distinct outcomes were generated through machine learning: Group 1 (n = 228): single ICC, size ≤ 5 cm, ALBI grade I, negative preoperative LN status; Group 2 (n = 708): (1) single tumor > 5 cm, (2) single tumor ≤ 5 cm, ALBI grade 2/3, and (3) single tumor ≤ 5 cm, ALBI grade 1, metastatic/suspicious LNs; Group 3 (n = 150): 2-3 tumors; Group 4 (n = 60): ≥ 4 tumors. 5-year OS among Group 1, 2, 3, and 4 patients was 60.5%, 35.8%, 27.5%, and 3.8%, respectively (p < 0.001). Similarly, 5-year disease-free survival (DFS) among Group 1, 2, 3, and 4 patients was 47%, 27.2%, 6.8%, and 0%, respectively (p < 0.001)., Conclusions: The machine-based CART model identified distinct prognostic groups of patients with distinct outcomes based on preoperative factors. Survival decision trees may be useful as guides in preoperative patient selection and risk stratification.

Intrahepatic cholangiocarcinoma(ICC) is the second most common primary liver cancer. The incidence of ICC has been significantly increased globally in recent years. The concealed onset of ICC usually results in late disease diagnosis. Liver resection is currently the only well-established treatment for ICC that may cure the disease, however, long-term survival rate is still unsatisfied due to the low resection rate and high recurrence rate. Local therapy combined with systemic chemotherapy is the main treatment for advanced or unresectable ICC, but the outcomes are still poor. With the in-depth understanding of the molecular mechanism of ICC and development of next-generation sequencing technology, multiple abnormal signaling pathways (RAS/MAPK, MET, EGFR) and gene mutations (FGFR2, IDH1/2) have been identified as potential therapeutic targets. Although there is still no approved targeted drugs for ICC, more than 100 clinical trials testing targeted therapy alone or in combination with chemotherapy are ongoing, among which some have shown promising application prospects. Molecular typing and personalized targeted therapy are important ways to improve the overall outcomes of ICC. This review summarized the recent advances in the targeted therapies for patients with ICC.

Context: Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA)., Aims: This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA., Settings and Design: We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013., Materials and Methods: Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group., Statistical Analysis Used: The Kaplan-Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model., Results: There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival., Conclusions: Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA., Competing Interests: None

Background: Little data regarding the selection of nonsurgical therapies for localized intrahepatic cholangiocarcinoma (ICC) are available., Methods: A cohort of nonsurgically managed patients with American Joint Commission on Cancer clinical stage I/II ICC in the United States from 2004 to 2013 were identified in the National Cancer Database. Overall survival (OS) was compared according to treatment options (radiofrequency ablation [RFA] vs chemoradiotherapy) using propensity-score matching., Results: Among 505 patients, 86 patients were treated with RFA and 419 patients were treated with chemoradiotherapy. After propensity matching (n = 84, each group), 5-year OS was 17.6% among patients who underwent RFA vs 3.8% among patients receiving chemoradiotherapy (P < .001). On bivariate analysis, RFA was related to an OS benefit (hazard ratio, 0.46; 95% confidence interval, 0.33-0.66; P < .001). Specifially, a stage-specific subgroup analysis revealed a survival benefit in favor of RFA among stage I patients (5-year OS; RFA: 20.1% vs chemoradiotherapy: 3.7%, P < .001), whereas no difference in OS was noted among patients with stage II disease., Conclusion: Among ICC patients with small (≤5 cm), solitary ICC without vascular invasion, RFA was associated with better survival compared with chemoradiotherapy., (© 2019 Wiley Periodicals, Inc.)

Background: Several studies have noted that the discriminatory ability and stratification performance of the AJCC 8th edition staging system is not entirely satisfactory. We aimed to improve the American Joint Committee on Cancer (AJCC) 8th edition staging system for intrahepatic cholangiocarcinoma (ICC)., Methods: A multicentric database from three Chinese mainland centers (n = 1601 patients) was used to modify the 8th edition staging system. This modified TNM (mTNM) staging system was then validated using the SEER database (n = 761 patients). A new TNM staging system, by incorporating serum tumor markers (TNMIS) into the mTNM staging system was then proposed., Results: The 8th edition staging system did not provide an adequate stratification of prognosis in the Chinese multicentric cohort. The mTNM staging system offered a better discriminatory capacity in the multicentric cohort than the original 8th edition. External validation in the SEER cohort showed that the mTNM staging system also had a good stratification performance. After further incorporating a serum marker stage into the mTNM staging, the TNMIS staging system was able to stratify prognosis even better., Conclusion: The proposed mTNM staging system resulted in better stratification performance and the TNMIS staging system provided even more accurate prognostic classification than the conventional TNM system., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Tumor burden is an important factor in defining prognosis among patients with primary and secondary liver cancers. Although the eighth edition of the American Joint Committee on Cancer staging system has changed the criteria for staging patients with intrahepatic cholangiocarcinoma to better define the effect of tumor burden on prognosis, the impact of intrahepatic cholangiocarcinoma tumor burden on overall survival has not been examined using a machine-learning tool., Methods: Patients who underwent resection of intrahepatic cholangiocarcinoma at 1 of 14 participating international hospitals between 1990 and 2015 were identified. Classical survival models and the Classification and Regression Tree model were used to identify groups of patients with a homogeneous risk of death and investigate the hierarchical association between variables and overall survival., Results: Among 1,116 patients included in the analysis, tumor size was ≤5 cm in 447 (40.1%) patients and >5 cm in 669 (59.9%) patients. Although 82.9% (n = 926) of patients had a single intrahepatic cholangiocarcinoma, 9.9% (n = 110) and 7.2% (n = 80) of patients had 2 and ≥3 tumors, respectively. Patients with intrahepatic cholangiocarcinoma tumors ≤5 cm and >5 cm had a 5-year overall survival of 51.7% and 32.6%, respectively (P < 0.001). Five-year overall survival decreased from 44.6% among patients with a single intrahepatic cholangiocarcinoma to 28.1% and 14.2% among patients with 2 and ≥3 intrahepatic cholangiocarcinomas, respectively (P < 0.001). Among the combinations of tumor size and intrahepatic cholangiocarcinoma tumor number used to estimate tumor burden, logarithmic transformation of tumor size (log tumor size) and intrahepatic cholangiocarcinoma tumor number had the highest concordance index. The Classification and Regression Tree model identified 8 classes of patients with a homogeneous risk of death, illustrating the hierarchical relationship between tumor burden (log tumor size and number of intrahepatic cholangiocarcinomas) and other factors associated with prognosis., Conclusion: Intrahepatic cholangiocarcinoma tumor size and number demonstrated a strong nonlinear association with survival after resection of intrahepatic cholangiocarcinoma. A log-model Classification and Regression Tree-derived tumor burden score may be a better tool to estimate prognosis of patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Multiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes after resection of ICC in patients with multiple foci., Methods: Patients who underwent resection for ICC between 1990 and 2017 were identified from 12 major HPB centers. Outcomes of patients with solitary lesions, multiple lesions (ML), and oligometastases (OM) were compared. OM were defined as extrahepatic metastases spread to a single organ., Results: One thousand thirteen patients underwent resection of ICC. On final pathology, 185 patients (18.4%) had ML and 27 (2.7%) had OM. Median survival of patients with a solitary tumor was 43.2 months, while the median survival of patients with 2 tumors was 21.2 months; the median survival of patients with 3 or more tumors was 15.3 months (p < 0.001). Five-year survival was 43.3%, 28.0%, and 8.6%, respectively. The median survival of patients without OM was 37.8 months versus 14.9 months among patients with OM (p < 0.001); estimated 5-year survival was 39.3% and 10.6%, respectively. In multivariable analysis, the presence of two lesions was not an independent poor prognostic factor for OS (HR 1.19; 95%CI 0.90-1.57; p = 0.229). However, the presence of three or more tumors was an independent poor prognostic factor for OS (HR 1.97; 95%CI 1.48-2.64; p < 0.001)., Conclusion: Resection of multiple liver tumors for patients with ICC did not preclude 5-year survival: in particular, estimated 5-year OS for resection of two tumors was 28.0%.

Background: The objective of the current study was to characterize patients with intrahepatic cholangiocarcinoma (ICC) undergoing curative-intent surgery with discordant preoperative and postoperative prediction scores and determine factors associated with prediction discrepancy., Methods: Patients who underwent hepatectomy for ICC between 1990 and 2016 were identified in a multi-institutional international database. Preoperative and postoperative prognostic models were designed and discordant prognostic scores were identified. A multivariable logistic regression analysis was completed to determined factors associated with score discordance., Results: Among 1149 patients, those who had concordant prediction scores were older (median age, 60 vs 56), and more likely to have a smaller median tumor size (6.0 vs 7.5 cm) (all P < .05). On multivariable logistic analysis, patients with higher neutrophil-lymphocyte ratio (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.09-1.19), higher CEA levels (OR, 1.25; 95% CI, 1.04-1.50), larger tumors (OR, 1.10; 95% CI, 1.04-1.15) and suspicious lymph nodes (OR, 2.05; 95% CI, 1.25-3.36) were more likely to have preoperative and postoperative score discordance. Older patients had decreased odds of having score discordance (OR, 0.98; 95% CI, 0.96-0.99). Patients with score discordance had worse overall survival compared with patients with concordant scores (median:15.9 vs 21.7 months, P < .05)., Conclusion: Score discordance may reflect an aggressive variant of ICC that would benefit from early integration of multidisciplinary treatment strategies., (© 2019 Wiley Periodicals, Inc.)

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Appropriate treatment of this aggressive and heterogeneous cancer requires accurate staging and prognostic stratification, as does patient selection for clinical trials. Over the past two decades, several staging systems and prognostic models for ICC have been developed. Most include independent prognostic factors such as tumor extent, clinical parameters and histopathological features and are inaccurate. Accumulating findings offer new insights into the genetic and molecular basis of ICC progression. Hence, staging systems and prognostic models that incorporate in clinicalpathological factors, molecular and genomic information, and tumor biomarkers, and hence more accurately estimate prognosis, will become a reality. This review summarizes the current staging systems and prognostic models for ICC and highlights the need to establish more precise and personalized systems and models that incorporate tumor biologic factors., (Copyright © 2019 Elsevier B.V. All rights reserved.)