Prognostic Factor For Intrahepatic Cholangiocarcinoma Research Articles

LI-RADS Category Can Be a Post-Surgical Prognostic Factor for Intrahepatic Cholangiocarcinoma in Patients with Liver Cirrhosis or Chronic Hepatitis B

<b><i>Introduction:</i></b> The Liver Imaging Reporting and Data System (LI-RADS) categorization has been proposed as a potential prognostic indicator for primary liver neoplasms in patients with liver cirrhosis or chronic hepatitis B. This multicenter study aimed to determine whether LI-RADS categorization can offer additional post-surgical prognostic value for intrahepatic cholangiocarcinoma (ICCA) when used in conjunction with the American Joint Committee on Cancer (AJCC) guidelines. <b><i>Methods:</i></b> Patients with high risk for hepatocellular carcinoma, surgically confirmed ICCAs, and available preoperative MRI were enrolled. LI-RADS categorization of ICCAs was performed using MRI features, and multivariate analyses were conducted incorporating LI-RADS category, AJCC staging, and clinicopathologic factors to evaluate their predictive value for postoperative recurrence-free survival (RFS) and overall survival (OS). In patients with early recurrence (<2 years), the percentages of AJCC stage I and LR-M or LR tumor-in-vein (TIV) were calculated, respectively. <b><i>Results:</i></b> Among the 166 ICCAs analyzed, 13.3% (22/166) were classified as LR-4/5, 77.7% (129/166) as LR-M, and 9.0% (15/166) as LR TIV. Classifications according to the 8th AJCC guidelines for patients with available post-surgical pathologic data and follow-up imaging were 40.6% (63/155) stage I tumors, 23.9% (37/155) stage II, and 35.5% (55/155) stage III. Multivariate analysis revealed that LI-RADS category (LR-M or LR-TIV) was a significant factor for predicting both RFS (hazard ratio [HR] = 2.86, <i>p</i> = 0.02) and OS (HR = 3.18, <i>p</i> = 0.03). Additionally, AJCC staging (II or III) was a significant factor for RFS (HR = 3.90, <i>p</i> < 0.001) and OS (HR = 3.29, <i>p</i> < 0.001), male sex was a significant factor for RFS (HR = 1.89, <i>p</i> = 0.006) and OS (HR = 2.23, <i>p</i> = 0.002), and positive resection margin was a significant factor for OS (HR = 1.91, <i>p</i> = 0.03). Among the 80 patients with early recurrence, 97.5% displayed LR-M or LR-TIV features, while 11.3% were AJCC stage I patients. <b><i>Conclusion:</i></b> The MRI-based preoperative LI-RADS categorization of ICCA provides additional post-surgical prognostic value beyond the AJCC guidelines, with significant implications for both RFS and OS.

Underexpression of Carbamoyl Phosphate Synthetase I as Independent Unfavorable Prognostic Factor in Intrahepatic Cholangiocarcinoma: A Potential Theranostic Biomarker.

Intrahepatic cholangiocarcinoma (IHCC) is the second most common malignant neoplasm of the liver. In spite of the increasing incidence worldwide, it is relatively rare in Western countries. IHCC is relatively common in Eastern and Southeastern Asia. Patients with IHCC are usually diagnosed at an advanced stage, therefore, the clinical outcome is dismal. Dysregulation of urea cycle metabolic enzyme expression is found in different types of cancers. Nevertheless, a comprehensive evaluation of genes related to the urea cycle (i.e., GO:0000050) has not been conducted in IHCC. By performing a comparative analysis of gene expression profiles, we specifically examined genes associated with the urea cycle (GO:0000050) in a publicly accessible transcriptomic dataset (GSE26566). Interestingly, CPS1 was identified as the second most prominently down-regulated gene in this context. Tumor tissues of 182 IHCC patients who underwent curative-intent hepatectomy were enrolled. The expression level of CPS1 protein in our IHCC cohort was assessed by immunohistochemical study. Subsequent to that, statistical analyses were carried out to examine the expression of CPS1 in relation to various clinicopathological factors, as well as to assess its impact on survival outcomes. We noticed that lower immunoreactivity of CPS1 in IHCC was associated with tumor progression (pT status) with statistical significance (p = 0.003). CPS1 underexpression was not only negatively correlated to overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS) in univariate analysis but also an independent prognosticator to forecast poorer clinical outcome for all prognostic indices (OS, DFS, LRFS and MeFs) in patients with IHCC (all p ≤ 0.001). These results support that CPS1 may play a crucial role in IHCC oncogenesis and tumor progression and serve as a novel prognostic factor and a potential diagnostic and theranostic biomarker.

THU-146 - Prognostic factors of intrahepatic cholangiocarcinoma after radical surgical resection

THU-146 - Prognostic factors of intrahepatic cholangiocarcinoma after radical surgical resection

Are FGFR and IDH1-2 alterations a positive prognostic factor in intrahepatic cholangiocarcinoma? An unresolved issue.

Despite representing some of the most common and investigated molecular changes in intrahepatic cholangiocarcinoma (iCCA), the prognostic role of FGFR and IDH1/2 alterations still remains an open question. In this review we provide a critical analysis of available literature data regarding this topic, underlining the strengths and pitfalls of each study reported. Despite the overall poor quality of current available studies, a general trend toward a better overall survival for FGFR2 rearrangements and, possibly, for FGFR2-3 alterations can be inferred. On the other hand, the positive prognostic role of IDH1/2 mutation seems much more uncertain. In this scenario, better designed clinical trials in these subsets of iCCA patients are needed in order to get definitive conclusions on this issue.

Evaluating prognostic value of biliary stone in intrahepatic cholangiocarcinoma by propensity score matching analysis.

Background: To explore biliary tract stone (BTS) as prognostic factors of intrahepatic cholangiocarcinoma (ICC). Methods: Clinical data of 985 ICC patients were classified into no BTS group and BTS group-subgrouped into hepatolithiasis (HL) and non-hepatolithiasis (NHL) group. Propensity score matching was utilized to mitigate baseline characteristics. Preoperative peripheral inflammation parameters (PPIP) were further investigated. Immunostaining of CD3, CD4, CD8, CD68, PD1 and PD-L1 were conducted. Results: Overall survival (OS) of patients without BTS surpassed BTS group (P = 0.040) while no difference of time to recurrence (TTR) was observed (P = 0.146). HL group had shorter OS and TTR than HL-matched group (P < 0.001 and P = 0.017, respectively) and survival time of NHL group differed not with NHL-matched group (P > 0.05). PPIP like neutrophils to lymphocytes ratio (NLR), platelet to lymphocyte ratio (PLR) and systemic immune inflammation (SII) of HL group exceeded no BTS group or NHL group (all P < 0.05). Associations of PPIP and tumorous immunocytes differed vastly among HL group, NHL group and no BTS group. Tumorous CD4+/CD3+ ratio and PD1+/CD3+ ratio of HL group surpassed those in no BTS group (P = 0.036 and P < 0.001, respectively) and NHL group (P = 0.015 and 0.002, respectively). Para-tumorous CD68+ macrophages exceeded that in tumor samples of HL group (P < 0.001). No difference of CD8+/CD3+ lymphocyte ratio and PD-L1 rank were detected. Conclusions: Hepatolithiasis, rather than extra-hepatic biliary stone, is a poor prognostic indicator of ICC. Immunotherapy is promising in treating HL-related ICC.

Prognostic impact of the metastatic lymph node number in intrahepatic cholangiocarcinoma

BackgroundLymph node metastasis in intrahepatic cholangiocarcinoma is a poor prognostic factor after radical surgery. However, unlike other biliary tract malignancies, the nodal stage of intrahepatic cholangiocarcinoma only reflects the presence of metastatic lymph nodes, not the number of metastatic lymph nodes. This study aimed to identify the prognostic impact of the metastatic lymph node number in intrahepatic cholangiocarcinoma. MethodsThe data from 87 patients with intrahepatic cholangiocarcinoma who had undergone hepatectomy with 5 or more harvested lymph nodes and covering stations 12 and 8 based on the previous criteria from January 2006 to December 2019 were retrospectively reviewed. The hazard ratio according to the increasing metastatic lymph node number was calculated with other known prognostic factors for intrahepatic cholangiocarcinoma. The patients were then divided into 3 groups according to the metastatic lymph node number (N0 [n = 45]: no metastatic lymph nodes; N+ <4 [n = 32]: 1 to 3 metastatic lymph nodes; N+ ≥4 [n = 10]: ≥4 metastatic lymph nodes). Disease-free survival and overall survival were also analyzed. ResultsThe metastatic lymph node number was a prognostic factor of oncologic survival (disease-free survival: hazard ratio = 1.18 [1.05–1.32], P = .005; overall survival: hazard ratio = 1.21 [1.06–1.37], P = .004). Survival analysis revealed significantly poorer outcomes with an increasing metastatic lymph node number (disease-free survival: N0 vs N+ <4 vs N+ ≥4: 36.0 [0.0–76.0] vs 8.0 [0.0–16.9] vs 2.0 [0.0–5.1] months, P < .001; overall survival: N0 vs N+ <4 vs N+ ≥4: 69.0 [24.5–113.5] vs 28.0 [18.9–37.1] vs 11.0 [6.4–15.6] months, P < .001). In post hoc analysis, a significant difference was found between adjacent groups (disease-free survival and overall survival: N+ <4 vs N+ ≥4, P = .001). ConclusionWith proper lymph node dissection, the number of metastatic lymph nodes is a prognostic factor of intrahepatic cholangiocarcinoma.

Prognostic Impact of Metastatic Lymph Node Numbers for Intrahepatic Cholangiocarcinoma

Background: Lymph node (LN) metastasis in intrahepatic cholangiocarcinoma (ICC) is one of the poor prognostic factors after radical surgery. However, unlike other biliary tract malignancies, the nodal stage of ICC only reflects the presence of metastatic LN, not the number of metastatic LNs. This study aims to identify the prognostic impact of metastatic LN numbers in ICC. Methods: Data from 102 ICC patients who underwent hepatectomy with 5 or more harvested LNs and covering stations No. 12 and 8 from January 2006 to December 2019 were retrospectively reviewed. Hazard ratio (HR) according to increasing metastatic LN number was calculated with other known prognostic factors for ICC. Using the result, the patients were divided into 3 groups according to the number of metastatic LNs (N0 group (n=50): no metastatic LN, N+<4 groups (n=39): 1-3 metastatic LNs, N+≥4 group (n=13): ≥4 metastatic LNs) and disease-free survival (DFS) and overall survival (OS) were analyzed. Results: Metastatic LN numbers were prognostic factors of oncologic survival. (DFS; HR=1.18[1.06-1.30], p=0.002, OS; HR=1.22[1.09-1.37], p=0.001) In the survival analysis, significantly poor outcomes were shown with an increasing number of metastatic LNs. (DFS; N0 vs. N+<4 vs. N+≥4: 36.0[0.0-76.9] vs. 9.0[2.9-15.1] vs. 2.0[0.6-3.4] months, p>0.001, OS; N0 vs. N+<4 vs. N+≥4: 69.0[30.6-107.4] vs. 26.0[21.3-30.7] vs. 10.0[7.7-12.3] months, p>0.001) In the post hoc analysis, a significant difference between adjacent groups was shown. (DFS and OS; N+<4 vs. N+≥4: p<0.001). Conclusion: With proper LN dissection, the number of metastatic LNs is a prognostic factor of ICC.Tabled 1EP01C-061Disease-free survivalOverall survivalUnivariateMultivariateUnivariateMultivariateHR (95%CI)p-valueHR (95%CI)p-valueHR (95%CI)p-valueHR (95%CI)p-valueT stage0.2280.3450.3040.375T43.69 (0.91-14.93)0.0683.79 (0.89-16.18)0.0723.09 (0.76-12.52)0.1152.72 (0.63-11.84)0.182T32.72 (1.10-6.76)0.0312.23 (0.88-5.66)0.0922.64 (1.05-6.60)0.0382.29 (0.89-5.88)0.084T22.33 (0.97-5.62)0.0601.80 (0.73-4.46)0.2042.18 (0.90-5.32)0.0851.54 (0.61-3.89)0.360T1b1.93 (0.70-5.33)0.2041.61 (0.55-4.72)0.3901.86 (0.68-5.13)0.2301.40 (0.47-4.15)0.540T1a(Reference)(Reference)(Reference)(Reference)Metastatic LN1.25 (1.15-1.35)<0.0011.18 (1.06-1.30)0.0021.28 (1.17-1.40)<0.0011.22 (1.09-1.37)0.001 Open table in a new tab

Lymph Node Metastasis Risk Evaluation and Clinical Meaning of Lymph Node Dissection in Intrahepatic Cholangiocarcinoma

Lymph node (LN) metastasis is an important prognostic factor in intrahepatic cholangiocarcinoma (IHCC). In this study, the clinical usefulness of LN dissection (LND) and the risk of LN metastasis were investigated.

Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma

Mutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.

Evaluation of nodal status in intrahepatic cholangiocarcinoma: a population-based study.

BackgroundLymph node metastasis (LNM) is a well-established prognostic factor for intrahepatic cholangiocarcinoma (ICC), but there are still some controversies relating to the evaluation of nodal status. Therefore, we investigated the role of lymph node dissection (LND), compared the prognostic performances of different nodal staging systems, and then developed and validated a nomogram to predict cancer-specific survival (CSS) of ICC patients.MethodsThe study cohort was taken from the Surveillance, Epidemiology, and End Results database. Akaike information criterion, Bayesian information criterion, Harrell’s C-index and area under the receiver operating characteristic curves were calculated to evaluate the different staging models. The nomogram for the CSS was constructed based on Cox regression models and validated by calibration curves. Decision curve analysis was introduced to examine the clinical value of the models.ResultsA total of 664 patients were enrolled, and 331 (51.4%) patients underwent LND. An increasing number of lymph nodes retrieved showed no oncologic benefit (P=0.876). LNM was identified in 103 (31.1%) patients, which was the cause of their poor prognoses (5-yr CSS 13.1% versus 44.9%, P<0.001). Patients without LNM could not benefit from adjuvant therapy after propensity score matching (P=0.140). Based on the Youden index, 4 or more lymph nodes retrieved might be adequate for accurate staging. The lymph node ratio (LNR) classification, with an optimal cut-off value of 0.15, displayed the best prognostic performance. Age, size, tumor number, T Stage, grade and the LNR classification were independent predictive factors for the CSS in ICC patients. The nomogram for predicting the CSS of ICC patients according to the independent factors was well calibrated and it showed better discrimination power and higher net benefits than the American Joint Committee on Cancer (8th edition) staging system.ConclusionsLNM is an independent prognostic factor in ICC. Although it shows no oncologic benefits, LND should still be considered as a method of stratifying patients, with 4 or more lymph nodes retrieved potentially enough to do so. LNR appears to be a promising and easy-to-use prognosticator for nodal staging. The constructed nomogram could serve as an effective tool to predict the CSS probabilities of ICC patients.

Synergistic impact of resection margin and microscopic vascular invasion for patients with HBV-related intrahepatic cholangiocarcinoma

ABSTRACT Objectives The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for intrahepatic cholangiocarcinoma (ICC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes. Methods A total of 711 consecutive patients who underwent curative liver resection for hepatitis B virus–related ICC were retrospectively analyzed. The different impact of the RM status (narrow, <1 cm, or wide, ≥1 cm) and MVI (positive, +, or negative, -) on overall survival (OS) and recurrence-free survival (RFS) were analyzed. Results The 1-, 3-, and 5-year OS rates were 67.6%, 42.5%, and 33.2% in wide RM & MVI (-), 58.0%, 36.1%, and 26.5% in narrow RM & MVI (-), 51.0%, 27.0%, and 24.3% in wide RM & MVI (+), and 39.0%, 20.4% and 14.3% in narrow RM & MVI (+) (p < 0.001). Multivariate analysis showed that RM & MVI were independent risk factors for the OS and RFS. Conclusion Combined analysis of RM and MVI can better stratify the risks of postoperative death and recurrence in patients with HBV-related ICC, which may help subsequent adjuvant therapy and closer follow-up.

Clinicopathological characteristics and prognostic factors for intrahepatic cholangiocarcinoma: a population-based study

We aimed to explore the clinicopathological features and survival-related factors for intrahepatic cholangiocarcinoma (ICC). Eligible data were extracted from the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2015. Totally, 4595 ICC patients were collected with a male to female ratio of nearly 1:1. The higher proportion of ICC patients was elderly, tumor size ≥ 5 cm and advanced AJCC stage. Most patients (79.2%) have no surgery, while low proportion of patients receiving radiotherapy (15.1%). The median survival was 7.0 months (range 0–153 months). The 5-year CSS and OS rates were 8.96% and 7.90%. Multivariate analysis found that elderly age (aged ≥ 65 years old), male, diagnosis at 2008–2011, higher grade, tumor size ≥ 5 cm, and advanced AJCC stage were independent factors for poorer prognosis; while API/AI (American Indian/AK Native, Asian/Pacific Islander) race, married, chemotherapy, surgery and radiotherapy were independent favorable factors in both CSS and OS. Furthermore, stratified analysis found that chemotherapy and radiotherapy improved CSS and OS in patients without surgery. Age, sex, race, years of diagnosis, married status, grade, tumor size, AJCC stage, surgery, chemotherapy and radiotherapy were significantly related to prognosis of ICC. Chemotherapy and radiotherapy could significantly improve survival in patients without surgery.

Peritumoral ductular reaction can be a prognostic factor for intrahepatic cholangiocarcinoma

BackgroundPeritumoral ductular reaction (DR) was reported to be related to the prognosis of combined hepatocellular-cholangiocarcinoma and hepatocellular carcinoma. Non-mucin-producing intrahepatic cholangiocarcinoma (ICC) which may be derived from small bile duct cells or liver progenitor cells (LPCs) was known to us. However, whether peritumoral DR is also related to non-mucin-producing ICCs remains to be investigated.MethodsForty-seven patients with non-mucin-producing ICC were eventually included in the study and clinicopathological variables were collected. Immunohistochemical analysis and immunofluorescence staining for cytokeratin 19, proliferating cell nuclear antigen, and α-smooth muscle actin were performed in tumor and peritumor liver tissues.ResultsA significant correlation existed between peritumoral DR and local inflammation and fibrosis. (r = 0.357, 95% CI, 0.037–0.557; P = 0.008 and r = 0.742, 95% CI, 0.580–0.849; P < 0.001, respectively). Patients with obvious peritumoral DR had high recurrence rate (81.8% vs 56.0%, P = 0.058) and poor overall and disease-free survival time (P = 0.01 and P = 0.03, respectively) comparing with mild peritumoral DR. Compared with the mild peritumoral DR group, the proliferation activity of LPCs/ cholangiocytes was higher in obvious peritumoral DR, which, however, was not statistically significant. (0.43 ± 0.29 vs 0.28 ± 0.31, P = 0.172). Furthermore, the correlation analysis showed that the DR grade was positively related to the portal/septalα-SMA level (r = 0.359, P = 0.001).ConclusionsPeritumoral DR was associated with local inflammation and fibrosis. Patients with non-mucin-producing ICC having obvious peritumoral DR had a poor prognosis. Peritumoral DR could be a prognostic factor for ICC. However, the mechanism should be further investigated.

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

BackgroundAccumulating amount of evidence has highlighted the important roles of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in tumor pathogenesis. However, the roles of long non coding RNAs (lncRNAs) in the lncRNA-related ceRNA network of intrahepatic cholangiocarcinoma (ICC) still remain enigmatic. The current study aims to identify prognostic factors in the lncRNA-related ceRNA network of ICC.MethodsThe transcriptome sequencing data of lncRNAs, messenger RNA (mRNA) and microRNA (miR) were downloaded from the SRA and TCGA databases. Differentially expressed lncRNAs (DElncRNAs), DEmiRs and DEmRNAs were identified and adopted to construct an lncRNA-miR-mRNA ceRNA network. ICC-associated DEmRNAs were adopted to construct the protein–protein interaction (PPI) network. The expression of the top 6 genes in the hub module was validated with mRNA transcriptome sequencing data and ICC-related gene expression dataset GSE45001, followed by GO and KEGG pathway enrichment analysis. The relationship between the hub gene-associated ceRNA network and the overall survival of patients with ICC was predicted by conducting a Kaplan–Meier survival analysis.ResultsSixty co-expressed DEmRNAs were identified in the ceRNA network. The top 6 hub genes consisted of downregulated FOS, IGF2, FOXO1 and NTF3, upregulated IGF1R, and insignificantly downregulated HGF in ICC tissues, when compared to that of normal adjacent tissues, followed by the successful construction of lncRNA-miR-hub network consisting of 86 ceRNA modules. MME-AS1 and hsa-miR-182 were associated with overall survival in ICC patients. FOS, IGF1R, IGF2, FOXO1, and NTF3 might target “TGF-β signaling pathway”, “the hedgehog signaling pathway”, “retinol metabolism”, or “type II diabetes mellitus” pathways respectively.ConclusionThese results indicate that FOS, IGF1R, IGF2, FOXO1, and NTF3 were useful prognostic factors in determining the prognosis of patients with ICC.

Perineural invasion as a prognostic factor for intrahepatic cholangiocarcinoma after curative resection and a potential indication for postoperative chemotherapy: a retrospective cohort study

BackgroundIn the past four decades, the incidence of cholangiocarcinoma, especially intrahepatic cholangiocarcinoma (ICC), has raised rapidly worldwide. Completeness of resection, max size of tumor and etc. are widely recognized as prognostic factors. However, the prognosis significance of perineural invasion (PNI) on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is controversial.MethodsICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Patients were grouped by existence of PNI and outcomes were compared between groups. The potential relationship between PNI and postoperative chemotherapy was also investigated.ResultsThere was no significant difference in demographic, clinical staging or tumor index between two groups, except positive hepatitis B surface antigen and CA19–9. PNI negative group showed a better prognosis in RFS (P < 0.0001) and OS (P < 0.0001). COX regression analyses showed PNI as an independent risk factor in RFS and OS. ICC with postoperative chemotherapy showed better effects in the whole cohort on both RFS (P = 0.0023) and OS (P = 0.0011). In PNI negative group, postoperative chemotherapy also showed significant benefits on RFS and OS, however not in PNI positive group (P = 0.4920 in RFS and P = 0.8004 in OS).ConclusionPNI was an independent risk factor in R0-resected ICC, presenting worse recurrence and survival outcomes. Meanwhile, negative PNI may act as an indication of postoperative chemotherapy.

Gender-Specific Disparity in Prognostic Factors and Survival Prediction for Intrahepatic Cholangiocarcinoma Undergoing Resection

Background: There is no information whether gender-associated prognostic factor disparity exists in patients with intrahepatic cholangiocarcinoma (ICC). Methods: A total of 732 ICC patients with pathological confirmation who underwent surgical resection between Nov 2011 and Apr 2015 was studied. Detection of prognostic factors was respectively performed for male and female patients using the Cox model. Gender-dependent nomograms were generated for survival prediction. Predictive performance was validated by receiver operating curves with area under curve (AUC) and calibration curves. Spearman’s rank correlation test was performed to identify gender-associated demographic and clinical factors. Results: There were 469 (64.1%) male and 263 (35.9%) female patients with ICC. Males achieved more favorable prognosis compared to females (overall survival; hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.48; P = 0.032; recurrence-free survival; HR, 1.12; 95% CI, 0.94-1.33; P = 0.197). Survival prediction was validated to be excellent for both genders (AUC, 0.71 and 0.68). Nomograms-stratified high risk showed a HR of 2.06 (P < 0.001) and 2.08 (P = 0.006) for male and female, respectively. Male showed nearest correlation with smoking, alpha fetoprotein, hepatitis B virus infection, and liver cirrhosis, whereas serum platelet count, tumor size, carbohydrate antigen (CA) 242, CA19-9, CA125, lymph node metastasis, and carcinoembryonic antigen were mostly correlated with female. Conclusions: There is a gender-associated disparity in prognostic factors for ICC after resection. Gender-dependent respective survival prediction seems to improve predictive accuracy. Large-scale prospective studies are needed to evaluate impact of gender on outcomes of other treatment modalities. Funding Statement: This work was supported by the National Natural Science Foundation of China (81772529, 81970453), the State Key Project of China (2017YFA0504503), International Science and Technology Cooperation Program of the Ministry of Science and Technology (2011DFA32980), National Key Basic Research Program of China 973 Program (2012CB526706). Declaration of Interests: The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Ethics Approval Statement: This study was approved by the local ethics committee and informed consents were obtained from all patients.

Long-term outcome and prognostic factors of intrahepatic cholangiocarcinoma involving the hepatic hilus versus hilar cholangiocarcinoma after curative-intent resection: Should they be recognized as perihilar cholangiocarcinoma or differentiated?

BackgroundPerihilar cholangiocarcinoma is defined as tumors arising predominantly at or near the biliary confluence, potentially consisting of two types: hilar cholangiocarcinoma (HC) and intrahepatic cholangiocarcinoma involving the hepatic hilum (hICC). However, whether hICC and HC should be strictly distinguished or combined remains highly controversial. We aimed to compare the clinicopathological characteristics, prognostic factors and long-term outcome of hICC versus HC after curative-intent resection. MethodsBetween January 1998 and June 2015, a total of 325 patients with hICC (n = 146) and HC (n = 179) who underwent curative-intent resection were enrolled. The medical records of these patients were retrospectively reviewed. ResultsPortal vein invasion, larger tumors, and later T stage were significantly more common in hICC group. A total of 110 (75.3%) hICC patients and 119 (66.5%) HC patients experienced tumor recurrences, respectively. The median recurrence-free survival (RFS) and overall survival (OS) of hICC patients were significantly worse than those of HC patients (median RFS, 14.3 versus 22.7 months, P = 0.014; median OS, 21.7 versus 30.6 months, P = 0.032). Multivariate analysis revealed tumor size, satellite nodules, surgical margin, and histological grade as independent factors for OS in hICC patients. On the other hand, the presence of liver parenchyma invasion, portal invasion, lymphovascular invasion, later N stage, and positive surgical margin were associated with shorter OS in HC patients. ConclusionshICC showed distinct clinicopathological features, more aggressive biological behaviors, different prognostic factors, and worse prognosis in comparison with HC. Therefore, making a strict distinction between hICC and HC is necessary.

Could hepatitis B vaccine act as an adjuvant to lower risk and relapses of cancer?

In this review article, we hypothesize that Hepatitis B Virus Vaccine (HBV-V) and certain antigens of Hepatitis B Virus (HBV) could act as anticancer immunoadjuvants in addition to their role of preventing HBV-associated liver cancer. Evidence suggests that in animal breast cancer and melanoma models, combining hepatitis B-surface antigen (HBsAg) with other cancer antigens resulted in enhanced antitumour activity. HBsAg shares antigenic mimicry with healthy and malignant cells including squamous epithelia, thymic epithelia, bladder- and colon cancer cells. There exist anecdotal reports and small case series about spontaneous remission of leukaemias and neuroblastoma following acute HBV-infection. Recent studies also exist showing HBV-carrier state is a good prognostic factor for intrahepatic cholangiocarcinoma. Further epidemiological studies and animal experiments are necessary whether HBV-Vs exert additional immunoadjuvant benefits besides lowering the risk of liver cancer.

Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignant tumor and has a poor prognosis. The prognostic factors associated with outcome remain poorly defined. In this study, we investigated the role of an important cell apoptosis initiator, Bcl-2 interacting mediator of cell death (Bim), by evaluating its expression and association with other clinicopathological features in ICCs. We analyzed 56 cases of ICC with clinical follow-up. The expression of Bim in ICC cells and other cellular components was evaluated by immunohistochemistry. Bim expression was considered up-regulated if Bim was detected in 10% or more of tumor cells. Of the 56 ICC samples, 19 (34%) had high Bim expression level, 15 (27%) were completely negative, and 22 (39%) were classified as low Bim expression (<10% positivity). Patients who had tumors with high Bim level had significantly longer overall survival than did those with low or no staining (median survival, 7.6 versus 2.6 years; hazard ratio, 0.40; P = .006). High Bim expression was also correlated with low Ki-67 index, and more importantly, none of the tumors with high Bim expression had lymph node metastases at the time of surgery. Our study demonstrates that Bim is an important and independent prognostic factor in ICC. Tumors with high Bim expression are associated with better prognosis through inhibiting tumor cell proliferation and metastatic ability. The development of new agents directly or indirectly targeting Bim may provide promising anticancer treatments.

Impact of serum carbohydrate antigen 19-9 level on prognosis and prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma.

Lymph node metastasis is an important prognostic factor for intrahepatic cholangiocarcinoma (ICC), but accurate preoperative diagnosis is difficult. The aim of this study was to measure the concentration of serum carbohydrate antigen 19-9 (s-CA19-9) as a preoperative predictor of lymph node metastasis. In our department, curative-intent hepatectomy for ICC has been performed only once the absence of metastases in para-aortic lymph nodes (PALN) has been confirmed from intraoperative frozen-section pathological examinations. The present study included 13 non-resected ICC patients with PALN metastasis (PALN group) and 44 resected ICC patients without PALN metastasis (non-PALN group). S-CA19-9 was examined to evaluate predictive performance for PALN metastasis and regional lymph node metastasis (pN1) from analysis of the receiver operating characteristic curve. In the non-PALN group, univariate and multivariate analyses for survival were performed on clinicopathological variables. From receiver operating characteristic curve analysis, s-CA19-9 showed good diagnostic accuracy for PALN metastasis (68%; cut-off, 200U/mL) and pN1 (77%; cut-off, 100U/mL). In univariate analysis, age (<65years), s-CA19-9 (≥100U/mL), portal vein resection, pN1, and positive resection margin (R1) were all identified as significant negative prognostic factors. Five-year survival rates of patients with high s-CA19-9 and pN1 were 6.9% and 7.3%, respectively. In multivariate analysis, high s-CA19-9 and R1 represented independent predictors of poor prognosis. Preoperative s-CA19-9 appears useful as a biomarker in patients with ICC, for predicting not only lymph node metastasis but also prognosis after surgical resection with curative intent.