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Background: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor with a poor prognosis. This study aimed to investigate whether Hemoglobin, Albumin, Lymphocytes, and Platelets (HALP) score and Tumor Burden Score (TBS) serves as independent influencing factors following radical resection in patients with ICC. Furthermore, we sought to evaluate the predictive capacity of the combined HALP and TBS grade, referred to as HTS grade, and to develop a prognostic prediction model. Methods: Clinical data for ICC patients who underwent radical resection were retrospectively analyzed. Univariate and multivariate Cox regression analyses were first used to find influencing factors of prognosis for ICC. Receiver operating characteristic (ROC) curves were then used to find the optimal cut-off values for HALP score and TBS and to compare the predictive ability of HALP, TBS, and HTS grade using the area under these curves (AUC). Nomogram prediction models were constructed and validated based on the results of the multivariate analysis. Results: Among 423 patients, 234 (55.3%) were male and 202 (47.8) were aged ≥ 60 years. The cut-off value of HALP was found to be 37.1 and for TBS to be 6.3. Our univariate results showed that HALP, TBS, and HTS grade were prognostic factors of ICC patients (all P < 0.05), and ROC results showed that HTS had the best predictive value. The Kaplan–Meier curve showed that the prognosis of ICC patients was worse with increasing HTS grade. Additionally, multivariate regression analysis showed that HTS grade, carbohydrate antigen 19–9 (CA19-9), tumor differentiation, and vascular invasion were independent influencing factors for Overall survival (OS) and that HTS grade, CA19-9, CEA, vascular invasion and lymph node invasion were independent influencing factors for recurrence-free survival (RFS) (all P < 0.05). In the first, second, and third years of the training group, the AUCs for OS were 0.867, 0.902, and 0.881, and the AUCs for RFS were 0.849, 0.841, and 0.899, respectively. In the first, second, and third years of the validation group, the AUCs for OS were 0.727, 0.771, and 0.763, and the AUCs for RFS were 0.733, 0.746, and 0.801, respectively. Through the examination of calibration curves and using decision curve analysis (DCA), nomograms based on HTS grade showed excellent predictive performance. Conclusions: Our nomograms based on HTS grade had excellent predictive effects and may thus be able to help clinicians provide individualized clinical decision for ICC patients. [ABSTRACT FROM AUTHOR]

Currently, there are still no definitive consensus in the treatment of intrahepatic cholangiocarcinoma (iCCA). This study aimed to build a clinical decision support tool based on machine learning using the Surveillance, Epidemiology, and End Results (SEER) database and the data from the Fifth Medical Center of the PLA General Hospital in China. 4,398 eligible patients from the SEER database and 504 eligible patients from the hospital data, who presented with histologically proven iCCA, were enrolled for modeling by cross-validation based on machine learning. All the models were trained using the open-source Python library scikit-survival version 0.16.0. Shapley additive explanations method was used to help clinicians better understand the obtained results. Permutation importance was calculated using library ELI5. All involved treatment modalities could contribute to a better prognosis. Three models were derived and tested using different data sources, with concordance indices of 0.67, 0.69, and 0.73, respectively. The prediction results were consistent with those under actual situations involving randomly selected patients. Model 2, trained using the hospital data, was selected to develop an online tool, due to its advantage in predicting short-term prognosis. The prediction model and tool established in this study can be applied to predict the prognosis of iCCA after treatment by inputting the patient's clinical parameters or TNM stages and treatment options, thus contributing to optimal clinical decisions. A prognostic model related to disease staging and treatment mode was conducted using the method of machine learning, based on the big data of multi centers. The online calculator can predict the short-term survival prognosis of intrahepatic cholangiocarcinoma, thus, help to make the best clinical decision. The online calculator built to calculate the mortality risk and overall survival can be easily obtained and applied. [ABSTRACT FROM AUTHOR]

Simple Summary: The noninvasive differentiation of hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC) remains challenging. In recent years, the number of studies on the application of radiomics in liver cancer has grown dramatically. However, there have been very few studies on the differentiation of HCC from ICC based on multisequence magnetic resonance imaging (MRI) radiomics. This study aimed to investigate the efficacy of a radiomics model based on pretherapeutic fat suppression T2-weighted imaging (FS-T2WI) and dynamic-contrast-enhanced MRI (DCE-MRI) features obtained from the arterial phase (AP) and portal venous phase (PVP) for noninvasively differentiating HCC from ICC. The purpose of this study was to investigate the efficacy of magnetic resonance imaging (MRI) radiomics in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC). The clinical and MRI data of 129 pathologically confirmed HCC patients and 48 ICC patients treated at the Affiliated Hospital of North Sichuan Medical College between April 2016 and December 2021 were retrospectively analyzed. The patients were randomly divided at a ratio of 7:3 into a training group of 124 patients (90 with HCC and 34 with ICC) and a validation group of 53 patients (39 with HCC and 14 with ICC). Radiomic features were extracted from axial fat suppression T2-weighted imaging (FS-T2WI) and axial arterial-phase (AP) and portal-venous-phase (PVP) dynamic-contrast-enhanced MRI (DCE-MRI) sequences, and the corresponding datasets were generated. The least absolute shrinkage and selection operator (LASSO) method was used to select the best radiomic features. Logistic regression was used to establish radiomic models for each sequence (FS-T2WI, AP and PVP models), a clinical model for optimal clinical variables (C model) and a joint radiomics model (JR model) integrating the radiomics features of all the sequences as well as a radiomics–clinical model combining optimal radiomic features and clinical risk factors (RC model). The performance of each model was evaluated using the area under the receiver operating characteristic curve (AUC). The AUCs of the FS-T2WI, AP, PVP, JR, C and RC models for distinguishing HCC from ICC were 0.693, 0.863, 0.818, 0.914, 0.936 and 0.977 in the training group and 0.690, 0.784, 0.727, 0.802, 0.860 and 0.877 in the validation group, respectively. The results of this study suggest that MRI-based radiomics may help noninvasively differentiate HCC from ICC. The model integrating the radiomics features and clinical risk factors showed a further improvement in performance. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are the most prevalent histologic types of primary liver cancer. HCC and ICC differ in treatment and prognosis, warranting an effective differential diagnosis between them. This study aimed to explore the clinical value of mean platelet volume (MPV) to discriminate between HCC and ICC. Material/methods: We performed a retrospective analysis of ICC and HCC patients who were from the Harbin Medical University Cancer Hospital, China. Logistic regression analysis was used to identify the independent factors for the differentiation of HCC and ICC. A receiver operating characteristic curve was built to evaluate the diagnostic performance of the potential model. An independent validation study was performed to validate the diagnostic ability. Results: ICC patients were detected in 146 out of 348 patients in the primary cohort. MPV levels were decreased in ICC patients compared with those in HCC patients. Logistic regression analysis revealed that MPV was an independent factor in distinguishing HCC from ICC. A combination of sex, hepatitis B surface antigen, MPV, alpha-fetoprotein, and carbohydrate antigen 19–9 demonstrated a good capability to differentiate HCC from ICC. Similar results were achieved in the validation cohort. Conclusions: MPV may be a new marker to help distinguish ICC from HCC. Further validation studies are required. [ABSTRACT FROM AUTHOR]

Background: Accurate prognosis assessment is essential for surgically resected intrahepatic cholangiocarcinoma (ICC) while published prognostic tools are limited by modest performance. We therefore aimed to establish a novel model to predict survival in resected ICC based on readily-available clinical parameters using machine learning technique.Methods: A gradient boosting machine (GBM) was trained and validated to predict the likelihood of cancer-specific survival (CSS) on data from a Chinese hospital-based database using nested cross-validation, and then tested on the Surveillance, Epidemiology, and End Results (SEER) database. The performance of GBM model was compared with that of proposed prognostic score and staging system.Results: A total of 1050 ICC patients (401 from China and 649 from SEER) treated with resection were included. Seven covariates were identified and entered into the GBM model: age, tumor size, tumor number, vascular invasion, number of regional lymph node metastasis, histological grade, and type of surgery. The GBM model predicted CSS with C-Statistics ≥ 0.72 and outperformed proposed prognostic score or system across study cohorts, even in sub-cohort with missing data. Calibration plots of predicted probabilities against observed survival rates indicated excellent concordance. Decision curve analysis demonstrated that the model had high clinical utility. The GBM model was able to stratify 5-year CSS ranging from over 54% in low-risk subset to 0% in high-risk subset.Conclusions: We trained and validated a GBM model that allows a more accurate estimation of patient survival after resection compared with other prognostic indices. Such a model is readily integrated into a decision-support electronic health record system, and may improve therapeutic strategies for patients with resected ICC. [ABSTRACT FROM AUTHOR]

Lenvatinib has been ratified as a first-line medication for advanced liver tumors by the American Food and Drug Administration. To assess the effectiveness and security of Lenvatinib in the Chinese population in a real-world setting, we enrolled 48 patients with unresectable liver cancer, managed from December 2018 to March 2021. Among them, 9 and 39 (83.30% men) patients had intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), respectively. Twenty-one (43.75%) patients had progressive disease after first-line treatment, and others (56.25%) had not receiving systemic treatment. Lenvatinib was administered alone or in combination with a programmed cell death protein 1 antibody (anti-PD-1). Treatment duration, median progression-free survival (mPFS), and median overall survival (mOS) were examined. The mOS and mPFS were 22.43 and 8.93 months, respectively. Of HCC patients treated with Lenvatinib only, the mOS and mPFS were 22.43 and 11.60 months, respectively. The corresponding values for HCC cases managed with anti-PD-1 combined with Lenvatinib were 21.77 and 7.10 months, respectively. ICC patients did not reach the mOS and their mPFS was 8.63 months. The present findings support the efficacy and security of Lenvatinib in the real-world therapy of Chinese patients with unresectable liver cancer. [ABSTRACT FROM AUTHOR]

Background: At present, hepatectomy is still the most common and effective treatment method for intrahepatic cholangiocarcinoma (ICC) patients. However, the postoperative prognosis is poor. Therefore, the prognostic factors for these patients require further exploration. Whether microvascular invasion (MVI) plays a crucial role in the prognosis of ICC patients is still unclear. Moreover, few studies have focused on preoperative predictions of MVI in ICC patients. Methods: Clinicopathological data of 704 ICC patients after curative resection were retrospectively collected from 13 hospitals. Independent risk factors were identified by the Cox or logistic proportional hazards model. In addition, the survival curves of the MVI-positive and MVI-negative groups before and after matching were analyzed. Subsequently, 341 patients from a single center (Eastern Hepatobiliary Hospital) in the above multicenter retrospective cohort were used to construct a nomogram prediction model. Then, the model was evaluated by the index of concordance (C-Index) and the calibration curve. Results: After propensity score matching (PSM), Child-Pugh grade and MVI were independent risk factors for overall survival (OS) in ICC patients after curative resection. Major hepatectomy and MVI were independent risk factors for recurrence-free survival (RFS). The survival curves of OS and RFS before and after PSM in the MVI-positive groups were significantly different compared with those in the MVI-negative groups. Multivariate logistic regression results demonstrated that age, gamma-glutamyl transpeptidase (GGT), and preoperative image tumor number were independent risk factors for the occurrence of MVI. Furthermore, the prediction model in the form of a nomogram was constructed, which showed good prediction ability for both the training (C-index = 0.7622) and validation (C-index = 0.7591) groups, and the calibration curve showed good consistency with reality. Conclusion: MVI is an independent risk factor for the prognosis of ICC patients after curative resection. Age, GGT, and preoperative image tumor number were independent risk factors for the occurrence of MVI in ICC patients. The prediction model constructed further showed good predictive ability in both the training and validation groups with good consistency with reality. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to investigate the survival outcomes of surgical margin width in intrahepatic cholangiocarcinoma (ICC).Methods: Between November 2011 and August 2017, patients who underwent hepatectomy for ICC were collected from 13 major hepatopancreatobiliary centers in China. The survival outcomes for patients who underwent wide margin hepatectomy (WMH) were compared with those who underwent narrow margin hepatectomy (NMH) using the 1:1 propensity score matching (PSM).Results: Among 478 included patients, 195 (40.8%) underwent WMH whereas 283 (59.2%) underwent NMH. PSM yielded 79 matched patients with similar baseline characteristics. Patients underwent WMH had a significant better OS and DFS compared with those underwent NMH (before PSM: median OS 27 vs 17 months, P < 0.05; median DFS 15 vs 8 months, P = 0.001, after PSM: median OS 41 vs 22 months, p < 0.05; median DFS 16 vs 10 months, p < 0.05). However, subgroup analysis based on the AJCC staging system, WMH could only improve the survival outcomes in AJCC I ICC patients (Stage I: OS, DFS, P<0.05).Conclusions: Surgeons should strive to achieve a wide surgical margin for patients with AJCC I ICC to optimize the long-term outcome. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatic and coagulation function are routine laboratory tests prior to curative hepatectomy. The prognostic value of gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR) and international normalized ratio (INR) in surgically treated patients with intrahepatic cholangiocarcinoma (ICC) remains unclear. Methods: ICC patients received curative hepatectomy in two west China centers were included. Time-dependent ROC curves were conducted to compare established indexes with prognostic value for ICC. GPR-INR score was introduced and evaluated using the Time-dependent AUC curve and Kaplan-Meier survival analysis. A novel nomogram based on the GPR-INR score was proposed; Harrell's C-index, calibration curve and decision curve analysis were used to assess this nomogram. Results: A total of 653 patients were included. The areas under ROC curves of GPR and INR in OS and RFS were superior to other indexes. Patients with a high GPR-INR score (1,2) presented significantly decreased overall survival (OS) and recurrence-free survival (RFS); GPR-INR sore, along with several clinicopathological indexes were selected into the nomogram, the calibration curve for OS probability showed good coincidence between the nomogram and the actual surveillance. The C-index of the nomogram was 0.708 (derivation set) and 0.746 (validation set), which was more representative than the C-indexes of the GPR-INR score (0.597, 0.678). In decision curve analysis, the net benefits of the nomogram in derivation and validation set were higher than Barcelona Clinic Liver Cancer staging (BCLC) classification and American Joint Committee on Cancer (AJCC) TNM 8th staging system. Conclusions: The proposed nomogram generated superior discriminative ability to established staging systems; it is profitable to applicate this nomogram in clinical practice. [ABSTRACT FROM AUTHOR]

Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC – associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells – was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4 , DNAH1, GLI2 , LIPE , MYH7 , RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors. [Display omitted] • EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. • EBVaICChas unique characteristics related to etiology, clinicopathology and molecular genetics. • Both PD-1 and PD-L1 in tumor-infiltrating lymphocytes and PD-L1 in tumor cells are overexpressed in EBVaICC. • Patients with EBVaICC may respond well to immune checkpoint inhibitors. • The lymphoepithelioma-like subtype of EBVaICC is related to favorable survival. [ABSTRACT FROM AUTHOR]

Background: The clinical value of lymph-node dissection (LND) for intrahepatic carcinoma (ICC) patients with clinically negative lymph node metastasis (LNM) remains unclear; hence we conducted a multi-center study to explore it. Methods: Patients who were diagnosed ICC with clinically negative LNM and underwent hepatectomy with or without LND from December 2012 to December 2015 were retrospectively collected from 12 hepatobiliary centers in China. Overall survival (OS) was analyzed using the Kaplan–Meier method, and then subgroup analysis was conducted stratified by variables related to the prognosis. Results: A total of 380 patients were eligible including 106 (27.9%) in the LND group and 274 (72.1%) in the non-LND group. Median OS in the LND group was slightly longer than that in the non-LND group (24.0 vs. 18.0 months, P = 0.30), but a significant difference was observed between the two groups (24.0 vs. 14.0 months, P = 0.02) after a well-designed 1:1 propensity score matching without increased severe complications. And, LND was identified to be one of the independent risk factors of OS (HR = 0.66, 95%CI = 0.46–0.95, P = 0.025). Subgroup analysis in the matched cohort showed that patients could benefit more from LND if they were male, age <60 years, had no HBV infection, with ECOG score <2, CEA ≤5 ug/L, blood loss ≤400 ml, transfusion, major hepatectomy, resection margin ≥1 cm, tumor size >5 cm, single tumor, mass-forming, no satellite, no MVI, and no perineural invasion (all P < 0.05). Furthermore, only patients with pathologically confirmed positive LNM were found to benefit from postoperative adjuvant therapy (P < 0.001). Conclusion: With the current data, we concluded that LND would benefit the selected ICC patients with clinically negative LNM and might guide the postoperative management. [ABSTRACT FROM AUTHOR]

Background and Aims: The prognosis of intrahepatic cholangiocarcinoma (ICC) after radical resection is far from satisfactory; however, the clinical value of adjuvant therapy (AT) remains controversial. This multicenter study aimed to evaluate the clinical value of AT and identify potential patients who would be benefited from AT. Methods: Data from ICC patients who underwent radical resection were retrospectively collected from 12 hepatobiliary centers in China between December 2012 and December 2015. Patients were divided into AT and non‐AT groups based on whether AT was administered or not. Overall survival (OS) and disease‐free survival (DFS) were analyzed using the Kaplan‐Meier method before and after 1:2 propensity score matching (PSM). Subgroup analyses were conducted based on the established staging systems. Results: A total of 412 patients were enrolled in this study, and 77 patients (18.9%) received AT, including 32 (7.8%) patients who received transarterial chemoembolization (TACE), 21 (5.1%) patients who received chemotherapy, 10 (2.4%) patients who received radiotherapy, and 14 (3.4%) patients who received adjuvant chemoradiotherapy. The median OS and DFS were both longer in the AT group than in the non‐AT group (43.0 months vs 21.0 months, P =.015; 16.0 months vs 11.0 months, P =.045, respectively), and the advantage of AT was confirmed for both the OS and DFS (P =.023; P =.046, respectively) after 1:2 PSM. Furthermore, based on the established nomogram, only "middle‐risk" patients receiving AT cherished a longer median OS (43.0 months vs 20.0 months, P =.033). In subgroup analyses that were stratified by different AT strategies, patients receiving postoperative chemotherapy had a longer median OS (37.0 months vs 21.0 months, P =.039), while patients receiving postoperative TACE had a longer median DFS (50.0 months vs 11.0 months, P =.007). Conclusion: With the current data, we conclude that AT benefits ICC patients following radical resection, especially those "middle‐risk" patients, as evaluated by the established nomogram. However, exactly which patients are the most suitable for AT requires further study and validation. [ABSTRACT FROM AUTHOR]

Aim The incidence and mortality associated with intrahepatic cholangiocarcinoma is increasing in many countries and documentation of disease outcome is sparse. The present study was undertaken to investigate the prognostic factors for intrahepatic cholangiocarcinoma (ICC) following surgical resection. The impact of pre-existing HBV virus infection and adjuvant chemotherapy on the overall survival was also evaluated. Methods Clinical and pathological data were collected retrospectively from 81 patients undergoing surgery for ICC between 2005 and 2011, at The Henan Province Tumor Hospital and the First Affiliated Hospital of Zheng Zhou University. Survival and prognosis were analyzed using the Kaplan-Meier method and COX regression model. Results The population included 37 patients who were HBsAg + or anti-HBc+, 21 patients who were anti-HBs + positive and 18 patients who received adjuvant chemotherapy. The overall 1- and 3-year survival rates were 51% and 20%, respectively. The median survival was 12.2 months. Univariate analysis identified the following prognostic factors: HBV virus infection or HBV vaccine prior to resection (P = 0.017); adjuvant chemotherapy (P = 0.001); preoperative serum CA19-9 (>200U/mL; P = 0.015); GGT (>64U/L; P = 0.008), ALP (>119U/L; P = 0.01); lymph node metastasis (P = 0.005); radical resection (P = 0.021); intrahepatic metastasis (P = 0.015) and diabetes (P = 0.07). Multivariate analysis identified chronic HBV infection (RR = 0.583; P = 0.041), anti-HBs positivity (RR = 0.680; P = 0.050), adjuvant chemotherapy (RR = 0.227; P < 0.001), lymph node metastasis (RR = 2.320; P = 0.001), and intrahepatic duct stones (RR = 0.473; P = 0.032) as independent prognostic factors. Conclusions HBV virus infection or HBV vaccination prior to resection, together with adjuvant chemotherapy, were independently associated with improved survival in patients undergoing surgery for ICC. [ABSTRACT FROM AUTHOR]

Background/Aims: The risk factors for cholangiocarcinoma are incompletely defined in China, especially for intrahepatic cholangiocarcinoma (ICC). We evaluated the risk factors for both ICC and extrahepatic cholangiocarcinoma (ECC). Methods: A case–control study in which cases were cholangiocarcinoma patients referred to Peking Union Medical College Hospital (PUMCH) between 1998 and 2008 and controls were healthy individuals. Controls were randomly selected from an existing database of healthy individuals at the Health Screening Center of PUMCH. Data on liver disease, family history, diabetes, smoking and drinking were collected by a retrospective review of the patients' records and health examination reports or by interview. Results: A total of 190 patients (61 ICC; 129 ECC) and 380 age- and sex-matched controls were enrolled. HBsAg ( P<0.001) and anti-HBc without HBsAg ( P=0.001) were significantly related to ICC. The adjusted odds ratios (OR) and 95% confidence intervals (CI) were 18.1 (95% CI: 7.5–44.0) and 3.6 (95% CI: 1.7–7.6) respectively. Diabetes mellitus ( P=0.007), cholecystolithiasis ( P=0.004) and previous cholecystectomy ( P<0.001) were significantly associated with ECC. The prevalence of cirrhosis was higher in ICC than that in ECC ( P<0.001). Furthermore, on excluding the ICC patients with cirrhosis, ICC patients showed significant independent associations with HBsAg (OR: 7.3; 95% CI: 3.1–17.2) and anti-HBc without HBsAg (OR: 2.4; 95% CI: 1.1–5.2). Conclusion: Cirrhosis and chronic hepatitis B virus infection are risk factors for ICC, while cholecystolithiasis, diabetes and previous cholecystectomy are risk factors for ECC. [ABSTRACT FROM AUTHOR]

Background & Aims: Sarcopenia is characterized by loss of skeletal muscle mass and associated with poor postoperative outcomes. This study aimed to investigate the prognostic value of preoperative albumin-globulin score (AGS), skeletal muscle index (SMI) as well as their combination in patients with intrahepatic cholangiocarcinoma (ICC) treated with surgical resection., Methods: A total of 613 newly diagnosed ICC patients from two centers were retrospectively analyzed (460 in discovery cohort and 153 in validation cohort). The plain computed tomography images were used to measure SMI. The effect of AGS, SMI and CAS grade on clinicopathological characteristics and long-term outcomes of patients with ICC were analyzed., Results: The SMI was significantly greater in males than in females. Patients with decreased AGS, increased SMI were associated with improved overall survival (OS) and recurrence-free survival (RFS). Stratefied by CAS grade, 68 (14.8%) patients in grade 1 were associated with increased body mass index (BMI) and best postoperative prognosis, whereas 194 (42.1%) patients in grade 3 were linked to worst OS and RFS. The CAS grade showed a promising accuracy in predicting OS and RFS of ICC patients (area under curves [AUCs] were 0.732 and 0.768). Multiple tumors, MVI and elevated CAS grades were identified as independent risk factors for OS and RFS of ICC patients. These results were confirmed by validation cohort., Conclusion: The present study provided compelling evidence that a novel index based on combination of preoperative AGS and SMI was closely related to postoperative long-term outcomes for surgically treated ICC patients. Preoperative evaluation of CAS grade may be useful for risk classification and clinical therapeutic decision-making for ICC patients., Competing Interests: Conflicts of interest The authors have declared no conflict of interest., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

As more and more molecular markers have been identified in Intrahepatic Cholangiocarcinoma (ICC), target treatments are promising all around the world. However, geographical and ethnic variations in the ICC epidemiology suggest different genetic variance prevalence in western and eastern countries. Six genetic variations in Chinese ICC populations were analyzed by fluorescent in situ hybridization (FISH) or Sanger sequencing, listed as IDH1/2 mutation, FGFR2 translocation, NTRK1 amplification, MDM2 amplification, HER2 amplification and MET amplification, all of which have corresponding target drugs; meanwhile, they were compared with these gene prevalence in Spanish population based on the cBioPortal database. The incidences of IDH1/2 mutation, FGFR2 translocation, NTRK1 amplification, MDM2 amplification, HER2 amplification and MET amplification were 29.5 %, 12.9 %, 1.51 %, 2.27 %, 3.03 % and 0.75 %, respectively, in the Spanish population and 7.14 %, 5.71 %, 7.86 %, 5.71 %,4.29 % and 2.14 %, respectively, in the Chinese population. For the gene NTRK1, 11 samples showed signal apart companied amplified using FISH break-apart probes but none of them demonstrated genetic fusion by next-generation sequencing. As to clinicopathological characteristics, patients carrying IDH1/2 mutation showed longer overall survival in the Chinese population, while those carrying FGFR2 translocation tended to be younger in the Spanish population. For HER2, MDM2 and MET, gene amplification predicted protein high-expression, whereas FGFR2 translocation and NTRK1 amplification did not predict protein high-expression. Although many target drugs have been speeded up for approval such as BGJ398 for FGFR2 fusion positive ICC patients in western countries, the beneficiary populations are very small in China. The regular target drug such as trastuzumab for HER2 amplification and Crizotinib for MET amplification may be potential candidates in target treatment based on the Chinese population. [ABSTRACT FROM AUTHOR]

Background: The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma., Methods: A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients., Results: Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence., Conclusions: The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

Background: The incidence of combined hepatocellular carcinoma-intrahepatic cholangiocarcinoma (cHCC-ICC) is relatively low, and the knowledge about the prognosis of cHCC-ICC remains obscure. In the study, we aimed to screen existing primary liver cancer staging systems and shed light on the prognosis and risk factors for cHCC-ICC., Methods: We retrospectively reviewed 206 cHCC-ICC patients who received curative surgical resection from April 1999 to March 2017. The correlation of survival measures with the histological types or with tumor staging systems was determined and predictive values of tumor staging systems with cHCC-ICC prognosis were compared., Results: The histological type was not associated with overall survival (OS) (P = 0.338) or disease-free survival (DFS) (P = 0.843) of patients after curative surgical resection. BCLC, TNM for HCC, and TNM for ICC stages correlated with both OS and DFS in cHCC-ICC (all P < 0.05). The predictive values of TNM for HCC and TNM for ICC stages were similar in terms of predicting postoperative OS (P = 0.798) and DFS (P = 0.191) in cHCC-ICC. TNM for HCC was superior to BCLC for predicting postoperative OS (P = 0.022) in cHCC-ICC., Conclusion: The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-ICC prognosis., (Copyright © 2020. Published by Elsevier B.V.)

Background: The genomic alterations of intrahepatic cholangiocarcinoma (ICC) in the Chinese population have not been fully revealed. Molecular profiling may provide a reference for clinical management, especially targeted therapy., Methods: A retrospective study was conducted in 122 ICC patients. All patients' samples underwent next-generation sequencing (NGS), which analyzed 417 genes. The genetic characteristics, clinical management and therapeutic responses were analyzed., Results: The most commonly mutated genes were TP53 (34%), KRAS (25%) and ARID1A (17%). Targeted agents were used referring to molecular profiling, in combination with chemotherapy. Twenty-two patients with wild-type KRAS/NRAS/BRAF were treated with cetuximab. The disease control and response rates were 78% and 47%, respectively, which were higher than those achieved with chemotherapy alone (72% and 11%, P = 0.16). Fifty-four patients underwent anti-VEGF treatment with bevacizumab. The disease control and response rates were 85% and 60%, respectively. Better therapeutic efficiency (P = 0.001) and longer progression-free survival (PFS) were observed in the bevacizumab-treated group compared to chemotherapy alone group (15.4 and 6.7 months, respectively; P = 0.04). The PFS of ten patients who underwent hepatectomy after combined treatment with chemotherapy and bevacizumab was longer than that of 139 patients who underwent surgical treatment (28.9 vs 18.0 months, P = 0.03). Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy., Conclusions: This study provides an overview of genetic alterations in Chinese ICC patients and indicates the potential clinical implications for NGS-based personalized therapies.

Objective: To evaluate the effect of perioperative inflammatory indicators on the prognosis of the patients with intrahepatic cholangiocarcinoma (ICC) after hepatectomy., Methods: The clinical data of 231 ICC patients in the West China Hospital of Sichuan University from December 2006 to December 2016 were retrospectively collected. Neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) and platelet-to-lymphocyte ratio (PLR) of patients during the perioperative period (pre-operation, postoperative day 3 and day 5) were analyzed. The X-tile software was used to determine the optimal cut-off values of NLR, d-NLR and PLR in pre-operation, postoperative day 3 and day 5. Based on the cut-off values, all patients were divided into high level group and low level group, and Kaplan-Meier methods were used to analyze the correlations of NLR, d-NLR and PLR with the disease-free survival (DFS) and overall survival (OS) of patients. Univariate and multivariate Cox regression models were applied to assess the prognostic values of NLR, d-NLR and PLR. Nomogram was established to predict the prognosis for ICC patients, and the predicting accuracy was evaluated by the Consistency index ( C -index)., Results: A total of 231 ICC patients including 115 males and 116 females were enrolled into this study, and the proportion of patients aged <60 years was 57.1%. Among the patients enrolled, 161 patients (69.7%) recurred and 156 patients (67.5%) died after hepatectomy. The median time of DFS and OS were 8.9 and 12.5 months respectively. The Kaplan-Meier curves showed that d-NLR and NLR levels in pre-operation, postoperative day 3 and day 5, together with the preoperative PLR level were correlated with the time of DFS ( P <0.05). Meanwhile, d-NLR and PLR levels in pre-operation, postoperative day 3 and day 5, together with the NLR level in pre-operation and postoperative day 3 were correlated with the time of OS ( P <0.05). Univariate and multivariate Cox regression model analysis suggested that high level of the preoperative NLR and d-NLR, together with the high level of NLR on postoperative day 3 were the independent influencing factors of poor DFS. High level of the preoperative NLR and d-NLR, together with the high level of NLR on postoperative day 3 were the independent influencing factors of OS. The level of PLR level was not correlated with DFS and OS. The C -index values of nomogram for predicting DFS and OS were 0.738 (95% confidence interval: 0.699-0.777) and 0.778 (95% confidence interval: 0.758-0.818), respectively., Conclusion: High level of the preoperative NLR, preoperative d-NLR and NLR on postoperative day 3 in ICC patients indicate poor prognosis, and PLR has no prognostic value for ICC patients after hepatectomy., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Background: The association between body mass index (BMI) and long-term outcomes of patients with ICC has not been well defined. We sought to define the presentation and oncologic outcomes of patients with ICC undergoing curative-intent resection, according to their BMI category., Methods: Patients who underwent resection of ICC were identified in a multi-institutional database. Patients were categorized as normal weight (BMI 18.5-24.9 kg/m 2 ), overweight (BMI 25.0-29.9 kg/m 2 ) and obese (BMI≥30 kg/m 2 ) according to the World Health Organization (WHO) definition. Impact of clinico-pathological factors on recurrence-free survival (RFS) was assessed using Cox proportional hazards model among patients in the three BMI categories., Results: Among a total of 790 patients undergoing curative-intent resection of ICC in the analytic cohort, 399 (50.5%) had normal weight, 274 (34.7%) were overweight and 117 (14.8%) were obese. Caucasian patients were more likely to be obese (66.7%, n = 78) and overweight (47.1%, n = 129) compared with Asian (obese: 18.8%, n = 22; overweight: 46%, n = 126) and other races (obese: 14.5%, n = 17; overweight: 6.9%, n = 19)(p < 0.001). There were no differences in the presence of cirrhosis (10.9%, vs. 12.8%, vs. 12.9%), preoperative jaundice (8.6% vs. 9.5% vs. 12.0%), or levels of CA 19-9 (75, IQR 24.6-280 vs. 50.9, IQR 17.9-232 vs. 43, IQR 16.9-192.7) among the BMI groups (all p > 0.05). On multivariable analysis, increased BMI was an independent risk factor for tumor recurrence (OR 1.16, 95% CI 1.02-1.32, for every 5 unit increase)., Conclusion: Increasing BMI was associated with incremental increases in the risk of recurrence following curative-intent resection of ICC. Future studies should aim to achieve a better understanding of BMI-related factors relative to prognosis of patients with ICC., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double-color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization. We further determined FGFR2 protein expression by immunohistochemistry and analyzed the clinicopathologic records of the patients. Eight tumors (6.6%) had FGFR2 translocations, whereas 15 (12.3%) had low-level FGFR2 amplification. Interestingly, the tumors that showed both translocation and low-level amplification frequently were of the mass-forming type. Compared with the ICCs with normal FGFR2s, tumors with amplifications secreted less mucus (P = .017) and typically were accompanied by hepatitis B virus infection (P = .004). Tumors with low-level amplification generally were of lower stage (P = .013) and associated with better overall survival (P = .017). As tumors with FGFR2 amplification exhibit different biology from lesions with a normal gene, low-level amplification of FGFR2 may play an important role in tumor progression and may be a marker for targeted therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Here, we investigate the potential factors that affect the outcome of patients with intrahepatic cholangiocarcinomas (ICC) and cirrhosis. We retrospectively reviewed the clinical data and pathological features of 58 patients with ICC and cirrhosis who underwent liver resection between July 2000 and March 2008, and analyzed the prognostic risk factors by means of univariate and multivariate analyses. The overall morbidity and mortality were 40% and 3.3%, respectively. The overall median survival was 24 months, and the 1-, 3-, and 5-year actuarial survival rates were 53%, 18%, and 10%, respectively. Univariate analysis showed that Child-Pugh classification, hypoalbuminemia, vascular invasion, lymphnodes metastasis, tumor-nodes-metastasis (TNM) staging system, positive surgical margins, and high perioperative blood transfusion volumes were all significantly associated with poor survival. Multivariate analysis confirmed that hypoalbuminemia, vascular invasion, positive surgical margins, and high perioperative blood transfusion volume were survival related, with hazard ratios (HR) of 2.58, 3.12, 3.57, and 1.98, respectively. Surgical resection is an effective treatment for patients affected by ICC and cirrhosis. Predictive factors, including hypoalbuminemia, vascular invasion, positive surgical margins, and high perioperative blood transfusion volumes are all related to poor survival.