Search

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_model_for_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.

Background While a certain degree of tumor infiltration of the portal vein is common in patients with perihilar cholangiocarcinoma (pCCA) scheduled for surgery, complete tumor-associated portal vein occlusion (PVO) is less frequently observed. Here, we analyzed the impact of PVO on perioperative and oncological outcomes in pCCA patients. Methods Between 2010 and 2019, 127 patients with pCCA underwent surgery in curative intent at our department of which 17.3% (22/127) presented with PVO. Extensive group comparisons were conducted and the association of cancer-specific (CSS) and disease-free survival (DFS) with PVO and other clinico-pathological characteristics were assessed using Cox regression models. Results Patients without PVO showed a median CSS of 65 months (3-year-CSS = 64%, 5-year-CSS = 53%) compared to 31 months (3-year-CSS = 43%, 5-year-CSS = 17%) in patients with PVO (p = 0.025 log rank). Patients with PVO did also display significant perioperative mortality (22.7%, 5/22) compared to patients without PVO (14.3%, 15/105, p = 0.323). Further, PVO (CSS: HR = 5.25, p = 0.001; DFS: HR = 5.53, p = 0.001) was identified as independent predictors of oncological outcome. Conclusions PVO has been identified as an important prognostic marker playing a role in inferior oncological outcome in patients with pCCA. As PVO is also associated with notable perioperative mortality, surgical therapy should be considered carefully in pCCA patients.

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. info:eu-repo/semantics/publishedVersion

This study aimed to investigate the impact of surgery on outcomes in patients with recurrent biliary tract cancer (BTC) and elucidate factors affecting survival after surgery for this disease.A single-center study was undertaken in 178 patients with recurrent BTC, of whom 24 underwent surgery for recurrence, 85 received chemotherapy, and 69 received best supportive care. Then, we carried out a multicenter study in 52 patients undergoing surgery for recurrent BTC (gallbladder cancer, 39%; distal cholangiocarcinoma, 27%; perihilar cholangiocarcinoma, 21%; intrahepatic cholangiocarcinoma, 13%).In the single-center study, 3-year survival after recurrence was 53% in patients who underwent surgery, 4% in those who received chemotherapy, and 0% in those who received best supportive care (p 0.001). Surgery was an independently prognostic factor (p 0.001). In the multicenter series, the respective 3-year and 5-year survival after surgery for recurrence was 50% and 29% in the 52 patients. Initial site of recurrence was the only independent prognostic factor (p = 0.019). Five-year survival after surgery for recurrence in patients with single distant, multifocal distant, and locoregional recurrence was 51%, 0%, and 0%, respectively (p = 0.002). Sites of single distant recurrence included the liver (n = 13, 54%), distant lymph nodes (all from gallbladder cancer, n = 7, 29%), lung (n = 2, 9%), peritoneum (n = 1, 4%), and abdominal wall (n = 1, 4%).Surgery may be an effective option for patients with less aggressive tumor biology characterized by single distant recurrence in recurrent BTC.

Background This study aimed to investigate the prognostic impact of parenchyma-sparing hepatectomy (PSH) on solitary small intrahepatic cholangiocarcinoma (ICC). Methods A total of 184 patients with solitary small ICC (≤ 5 cm) from 2009 to 2017 were included. Short- and long-term outcomes were compared between PSH and Non-PSH approach. Results 95 (51.6%) patients underwent PSH and 89 (48.4%) patients underwent Non-PSH for solitary small ICC. PSH was associated with less intraoperative blood loss (212.9 mL versus 363.5 mL, P=0.038), lower transfusion rate (7.4% versus 16.9%, P=0.048), without increasing the frequency of tumor recurrence (60.0% versus 58.4%). No significant differences were observed in overall survival (OS), recurrence-free survival (RFS) and liver RFS (P = 0.627, 0.769 and 0.538, respectively). 109 (59.2%) patients experienced recurrence, of these, 67 (36.4%) were intrahepatic recurrence. Subgroup analysis of patients with liver-only recurrence demonstrated an increased likelihood of repeat hepatectomy for PSH compared to Non-PSH (21.2% versus 2.9%, P = 0.031), thus resulting in improved liver OS (P = 0.016). Conclusion PSH was associated with improved perioperative outcomes but it did not increase liver recurrence rates. PSH offered an increased rate of salvage hepatectomy for recurrent tumor, thus improving long-term survival in cases in which liver recurrence occurred.

Background The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset. Furthermore, it sought to identify common prognostic factors across models, and assess methodological quality of the studies in which the models were developed. Methods The PRISMA guidelines were followed. External validation studies of prognostic models for patients with iCCA were searched in 5 databases. Model performance was assessed by discrimination and calibration. Results Thirteen external validation studies were identified, validating 18 different prognostic models. The Wang model was the sole model with good performance (C-index above 0.70) for overall survival. This model incorporated tumor size and number, lymph node metastasis, direct invasion into surrounding tissue, vascular invasion, Carbohydrate antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Methodological quality was poor in 11/12 statistical models. The Wang model had the highest score with 13 out of 17 points. Conclusion The Wang model for prognosis after resection of iCCA has good quality and good performance at external validation, while most prognostic models for iCCA have been developed with poor methodological quality and show poor performance at external validation.

Intrahepatic cholangiocarcinoma (iCCA) is subclassified into mass-forming (MF), periductal-infiltrative (PI), and mixed types grossly; however, their clinicopathological significance remains controversial.Clinicopathological characteristics of iCCA gross types were analysed according to histopathological type (small-duct, large-duct, indeterminate) or cholangiolocellular differentiation trait (CDT) in 108 iCCAs. The expression levels of inflammation-marker (CRP, FGB) and proliferation-marker (phospho-ERK1/2, Ki-67) were evaluated by immunohistochemistry.There were 87 MF, 8 PI, and 13 mixed-gross type. Small-duct-type (39, 44.8%) and CDT (19, 21.8%) were found only in MF-gross type. The inflammation-marker expression was higher in MF-type than in PI- and mixed-gross types (P = 0.023). It was high in small-duct-type, middle in indeterminate-type, and low in large-duct-type (P = 0.015), and iCCAs with CDT showed higher inflammation-marker expression compared to those without (P 0.001). Proliferation-marker expression did not differ according to gross type; however it was lower in iCCA with CDT compared to those without (P = 0.004). Subgrouping of the gross type according to histopathological type or CDT revealed that MF-type with small-duct-type or CDT had better overall survival compared to the others (P 0.05).MF-type iCCA is more heterogeneous than other gross types. High inflammation-marker/low proliferation-marker expression in MF-type with CDT or small-duct-type may be related to a good outcome.

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.

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.

The objective of this meta-analysis was to evaluate the effectiveness and safety of lymph node dissection (LND) in patients with intrahepatic cholangiocarcinoma (ICC).A literature search with a date range of January 2000 to January 2018 was performed to identify studies comparing lymph node dissection (LND+) with non-lymph node dissection (LND-) for patients with ICC. The LND + group was further divided into positive (LND + N+) and negative (LND + N-) lymph node status groups based on pathological analysis.13 studies including 1377 patients were eligible. There were no significant differences in overall survival (OS) (HR 1.13, 95% CI 0.94-1.36; P = 0.20), disease-free survival (DFS) (HR 1.23, 95% CI 0.94-1.60; P = 0.13), or recurrence (OR 1.39, 95% CI 0.90-2.15; P = 0.14) between LND + group and LND-group. Postoperative morbidity was significantly higher in the LND + group (OR 2.67, 95% CI 1.74-4.10; P 0.001). A subset analysis showed that OS was similar between LND + N- and LND-groups (HR 1.13, 95% CI 0.82-1.56; P = 0.450). However when comparing, OS of the LND-group to the LND+N+ group there was a significant increase in OS for the LND-group (HR 3.26, 95% CI 1.85-5.76; P 0.001).LND does not seem to positively affect overall survival and is associated with increased post-operative morbidity.

Background Growing evidence has suggested that intrahepatic cholangiocarcinoma (iCCA) can be classified into small- and large-duct types. The present study aimed to elucidate how large-duct iCCA is similar and dissimilar to perihilar cholangiocarcinoma (pCCA). Methods The study cohort consisted of iCCA (n = 58) and pCCA (n = 44). After iCCA tumors were separated into small- (n = 36) and large-duct (n = 22) types based on our histologic criteria, genetic statuses of the three types of neoplasms were compared. Locations of iCCA were plotted on a three-dimensional image and their distances from the portal bifurcation were measured. Results Large-duct iCCA was distinct from small-duct iCCA in terms of frequency of bile duct reconstruction required, perineural infiltration, and survival, with these features more similar to pCCA. Large-duct iCCA and pCCA more frequently had the loss of SMAD4 expression and MDM2 amplifications than small-duct iCCA, whereas the loss of BAP1 expression and IDH1 mutations were mostly restricted to small-duct iCCA. From imaging analysis, most tumors of large-duct iCCA were present around the second branches of the portal vein. Conclusion Large-duct type iCCA shared the molecular features with pCCA, and it may be reasonable to expand the definition of pCCA to include cancers originating from the second bile duct branches.

This study aimed to clarify the prognostic significance of neutrophil/prealbumin ratio index (NPRI) for overall survival (OS) and recurrence free survival (RFS) of ICC after curative surgery.Two-hundred and seventy-six ICC patients who underwent curative resection from December 2006 to April 2017 were recruited and analyzed retrospectively. The correlations between clinicopathological features and NPRI were analyzed. OS and RFS were calculated using Kaplan-Meier curve, and cox univariate and multivariate analyses were used to identify the prognostic factors.The optimal cut-off value of NPRI determined by ROC curve was 1.74 and the patients were divided into high-value and low-value groups. High-value NPRI was associated with higher risk of postoperative complications (p = 0.035) and longer hospitalization (p = 0.004).Univariate and multivariate cox analyses demonstrated that NPRI was an independent predictor for OS (p = 0.015) and RFS (p = 0.004) in ICC after curative resection. Furthermore, NPRI was also a significant predictor for OS and RFS in different subgroups of ICC, including CA19-935U/mL, single tumor, no vascular invasion, no local invasion and AJCC stages I + II.NPRI was an independent prognostic predictor for ICC after curative resection. It would have high clinical values due to its convenience.

Background Recurrent pyogenic cholangitis (RPC) is a known risk factor for intrahepatic cholangiocarcinoma (ICC), whether it represents a poor prognostic factor remains controversial. The aim of this study was to investigate the post-hepatectomy oncological outcomes of patients with ICC and coexisting RPC. Method A retrospective analysis with propensity score matching (PSM) was performed for comparison between ICC patient with and without RPC. Results There were 143 patients with ICC with a median follow-up of 21 months. RPC was diagnosed in 18% of patients. The time from RPC diagnosis to ICC diagnosis was 137(47–481) months. The 3-year disease-free (DFS) and overall survival for the whole population was 34% and 43% respectively. Preoperative child score, elevated carcinoembryonic antigen, presence of microvascular invasion, multiple tumours, presence of postoperative complications and RPC were independent factors for DFS and OS. After PSM, 60 ICC patients who did not have RPC were compared with 20 ICC patients with RPC. Patients with RPC had significantly worse median DFS (10 vs 23 months, P = 0.020) and OS (15 vs 45 months, P = 0.004) when compared to the patients without RPC. Conclusion RPC represents a poor prognostic factor affecting outcomes after hepatectomy for patients with ICC.

Background Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). Methods The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. Results Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). Conclusion The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.

Background: While several prognostic models have been developed to predict long-term outcomes in resectable intrahepatic cholangiocarcinoma (ICC), their prognostic discrimination remains limited. The addition of tumor markers might improve the prognostic power of the classification schemas proposed by the AJCC 8th edition and the Liver Cancer Study Group of Japan (LCSGJ). Methods: The prognostic discrimination of the AJCC and the LCSGJ were compared before and after the addition of CA 19-9 and CEA, using Harrell's C-index, net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) in an international, multi-institutional cohort. Results: Eight hundred and five surgically treated patients with ICC that met the inclusion criteria were identified. On multivariable analysis, CEA5 ng/mL, 100IU/mL CA 19-9< 500IU/mL and CA 19-9500 IU/mL were associated with worse overall survival. The C-index of the AJCC and the LCSGJ improved from 0.540 to 0.626 and 0.553 to 0.626, respectively following incorporation of CA 19-9 and CEA. The NRI and IDI metrics confirmed the superiority of the modified AJCC and LCSGJ, compared to the original versions. Conclusion: The inclusion of preoperative CA 19-9 and CEA in the AJCC and LCSGJ staging schemas may improve prognostic discrimination among surgically treated patients with ICC. info:eu-repo/semantics/publishedVersion

BACKGROUND: The benefit of adjuvant chemotherapy for resected intrahepatic cholangiocarcinoma (ICC) is unclear. The aim of the current study was to investigate the impact of adjuvant chemotherapy on survival among patients undergoing resection of ICC using a multi-institutional database. METHODS: 1154 ICC patients undergoing curative-intent hepatectomy between 1990 and 2015 were identified from 14 institutions. Cox proportional hazard modeling was used to determine the impact of adjuvant chemotherapy on overall survival (OS). RESULTS: Following resection, 347 (30%) patients received adjuvant chemotherapy, most commonly a gemcitabine-based regimen (n = 184, 52%). Patients with T2/T3/T4 disease were more likely to receive adjuvant therapy compared with patients with T1a/T1b disease (OR 2.5, 95%CI 1.89-3.23; P < 0.001). Among patients who did and did not receive adjuvant therapy, patients with T2/T3/T4 tumors had a 5-year OS of 37% (95%CI 28.9-44.4) versus 30% (95%CI 23.8-35.6), respectively (p = 0.006). Similarly patients with N1 disease who received adjuvant chemotherapy tended to have improved 5-year OS (18.3%, 95%CI 9.0-30.1 vs. no adjuvant therapy 12%, 95%CI 3.9-24.4; P = 0.050). CONCLUSIONS: While adjuvant chemotherapy did not influence the prognosis of all ICC patients following surgical resection, it was associated with a potential survival benefit in subgroups of patients at increased risk for recurrence, such as those with advanced tumors. info:eu-repo/semantics/publishedVersion