Outcomes Of Intrahepatic Cholangiocarcinoma Research Articles

Has Management of Intrahepatic Cholangiocarcinoma Evolved with the Evidence? Trends and Practice Patterns from the National Cancer Database.

Management of intrahepatic cholangiocarcinoma (IHC) has advanced in recent decades, including randomized trial evidence supporting systemic therapy in the palliative and adjuvant setting. Mounting observational evidence suggests resection of IHC with multifocal disease (IHC-MF) or lymph node metastasis (IHC-LNM) should be limited. It is unknown how real-world practice has evolved in light of research advances. This study characterizes trends in management and outcomes of IHC without distant metastasis. We queried the National Cancer Database (NCDB) for patients treated for IHC without distant metastasis (M0) and identified subgroups with lymph node (cN1) or multifocal hepatic involvement (cT2b). Two-sided Cochran-Armitage tests evaluated trends in initial treating modality and perioperative chemotherapy. Logistic regression evaluated associations with choice of initial treating modality. Overall survival (OS) was evaluated by using Kaplan-Meier methods. Between 2004 and 2020, 11,368 patients were treated for IHC without extrahepatic metastasis. Forty-three percent underwent resection. Initial management shifted from resection towards radiation or systemic therapy in IHC-MF and IHC-LNM. Use of perioperative chemotherapy increased from 39% pre-2010 to 70% in 2018-2020 (p < 0.001), most often delivered postoperatively. Across the entire cohort, median OS improved from 16 (95% confidence interval [CI] 15-18) to 27 months (95% CI 26-29). More modest improvements were observed in IHC-MF and IHC-LNM. Use of perioperative chemotherapy has been widely adopted, predating randomized trial evidence in the adjuvant setting. Initial management of IHC-MF and IHC-LNM has shifted from resection to systemic and/or radiation therapy. While OS has improved overall, outcomes of IHC-MF and IHC-LNM remain poor, warranting further investigation.

Construction and validation of a novel tumor morphology immune inflammatory nutritional score (TIIN score) for intrahepatic cholangiocarcinoma: a multicenter study

BackgroundTumor morphology, immune function, inflammatory levels, and nutritional status play critical roles in the progression of intrahepatic cholangiocarcinoma (ICC). This multicenter study aimed to investigate the association between markers related to tumor morphology, immune function, inflammatory levels, and nutritional status with the prognosis of ICC patients. Additionally, a novel tumor morphology immune inflammatory nutritional score (TIIN score), integrating these factors was constructed.MethodsA retrospective analysis was performed on 418 patients who underwent radical surgical resection and had postoperative pathological confirmation of ICC between January 2016 and January 2020 at three medical centers. The cohort was divided into a training set (n = 272) and a validation set (n = 146). The prognostic significance of 16 relevant markers was assessed, and the TIIN score was derived using LASSO regression. Subsequently, the TIIN-nomogram models for OS and RFS were developed based on the TIIN score and the results of multivariate analysis. The predictive performance of the TIIN-nomogram models was evaluated using ROC survival curves, calibration curves, and clinical decision curve analysis (DCA).ResultsThe TIIN score, derived from albumin-to-alkaline phosphatase ratio (AAPR), albumin–globulin ratio (AGR), monocyte-to-lymphocyte ratio (MLR), and tumor burden score (TBS), effectively categorized patients into high-risk and low-risk groups using the optimal cutoff value. Compared to individual metrics, the TIIN score demonstrated superior predictive value for both OS and RFS. Furthermore, the TIIN score exhibited strong associations with clinical indicators including obstructive jaundice, CEA, CA19-9, Child–pugh grade, perineural invasion, and 8th edition AJCC N stage. Univariate and multivariate analysis confirmed the TIIN score as an independent risk factor for postoperative OS and RFS in ICC patients (p < 0.05). Notably, the TIIN-nomogram models for OS and RFS, constructed based on the multivariate analysis and incorporating the TIIN score, demonstrated excellent predictive ability for postoperative survival in ICC patients.ConclusionThe development and validation of the TIIN score, a comprehensive composite index incorporating tumor morphology, immune function, inflammatory level, and nutritional status, significantly contribute to the prognostic assessment of ICC patients. Furthermore, the successful application of the TIIN-nomogram prediction model underscores its potential as a valuable tool in guiding individualized treatment strategies for ICC patients. These findings emphasize the importance of personalized approaches in improving the clinical management and outcomes of ICC.

Extrahepatic cholangiocarcinoma: Genomic variables associated with anatomical location and outcome.

554 Background: Genomic determinants of outcome in intrahepatic cholangiocarcinoma have become clear but remain ill-defined in extrahepatic cholangiocarcinoma (ECA). We aimed to clarify the genomic alterations that define ECA, analyze differences between perihilar (PCA) and distal (DCA) disease, and determine clinicopathologic and genomic factors associated with survival. Methods: Patients with EHC with tissue available for targeted next-generation sequencing at Memorial Sloan Kettering Cancer Center were identified. Differences between PCA and DCA were compared, stratified by disease extent and treatment. Associations between genomic alterations and clinicopathologic features and outcomes were analyzed. Univariable and then multivariable cox proportional hazards regression were used to compare survival, which was reported from operation in resected patients and from diagnosis in non-resected patients. Results: Two-hundred-twenty-four patients (n=127 PCA, n=97 DCA, 2006-2022) met inclusion criteria. Median survival was 29 months (IQR [25, 35]; 43 months [35, 48] resection, 17 months [13, 19] without). Compared to PCA, DCA was enriched in TP53mut (67 [69%] vs. 42 [33%]), Q&lt;0.01) and epigenetic pathway alterations (44 [45%] vs. 37 [29%], Q=0.041) and had more altered pathways (3 vs. 2, Q&lt;0.01). KRASmut was similar between PCA (46 [36%]) and DCA (36 [37%]); however, PCA was enriched in KRAS G12V (16 [13%] vs. 4 [4%]) and Q61H (11 [9%] vs. 3 [3%], P=0.002). No other clinicopathologic or genomic variables distinguished PCA from DCA (Table). MDM2mut occurred in 19/141 (13%) patients with nodal/metastatic disease compared to 1/83 (1%) patients with local disease ( Q=0.03), but conferred no survival disadvantage. In resected patients, survival was similar between PCA and DCA and no genomic alterations were associated with outcome. By contrast, in patients without surgery, CDKN2Adel (HR 2.59, 95% CI [1.48, 4.52]) and APCmut (HR 5.11, 95% CI [1.96, 13.3]) were associated with survival disadvantages. Lack of resection (HR 3.13, 95% CI [2.25, 4.36]), CDKN2Amut (HR 1.80 [95% CI 1.80, 2.68), and APCmut (HR 2.00 [95% CI 1.04, 3.87]) were associated with poor survival in the entire cohort. Conclusions: In this study, aside from a higher incidence of TP53mut in DCA and some differences in KRAS subtype alteration patterns, genomic alterations were comparable between PCA and DCA. CDKN2Amut and APCmut were associated with poor survival in all patients but no biomarkers provided significant prognostic information when tumors were resected. [Table: see text]

Nationwide treatment and outcomes of intrahepatic cholangiocarcinoma

BackgroundMost data on the treatment and outcomes of intrahepatic cholangiocarcinoma (iCCA) derives from expert centers. This study aimed to investigate the treatment and outcomes of all patients diagnosed with iCCA in a nationwide cohort. MethodsData on all patients diagnosed with iCCA between 2010 and 2018 were obtained from the Netherlands Cancer Registry. ResultsIn total, 1747 patients diagnosed with iCCA were included. Resection was performed in 292 patients (17%), 548 patients (31%) underwent palliative systemic treatment, and 867 patients (50%) best supportive care (BSC). The OS median and 1-, and 3-year OS were after resection: 37.5 months (31.0–44.0), 79.2%, and 51.6%,; with systemic therapy, 10.0 months (9.2–10.8), 38.4%, and 5.1%, and with BSC 2.2 months (2.0–2.5), 10.4%, and 1.3% respectively. The resection rate for patients who first presented in academic centers was 33% (96/292) compared to 13% (195/1454) in non-academic centers (P < 0.001). DiscussionHalf of almost 1750 patients with iCCA over an 8 year period did not receive any treatment with a 1-year OS of 10.4%. Three-year survival was about 50% after resection, while long-term survival was rare after palliative treatment. The resection rate was higher in academic centers compared to non-academic centers.

Impact of Medicaid Expansion on the Treatment and Outcomes of Intrahepatic Cholangiocarcinoma

IntroductionThe Affordable Care Act increased insurance coverage for patients residing in states that expanded Medicaid coverage, but its impact on the outcomes of intrahepatic cholangiocarcinoma (ICC) is not clear. Therefore, we examine the impact of Medicaid expansion (ME) on access to treatment and outcomes of ICC. MethodsWe queried the National Cancer Database (NCDB) data for patients with a diagnosis of ICC (2010–2018). Difference-in-difference (DID) analysis was performed to assess the impact of January 2014 ME on curative-intent surgical resection, multimodal therapy, neoadjuvant chemotherapy, 30-day mortality, and overall survival (OS). ResultsOf the 2150 patients included in the study,1574 (73.2%) and 576 (26.8%) patients lived in non-ME and ME states, respectively. On adjusted DID, ME was independently associated with receipt of curative-intent surgical resection (DID coefficient: 0.05, 95% confidence interval [95% CI]: 0.04–0.06, p = 0.002) and multimodal therapy (DID coefficient: 0.08, 95% CI: 0.06–0.10, p = 0.004). In addition, ME was associated with improved OS in ME states (hazard ratio [HR]: 0.73, 95% CI: 0.62–0.87, p = 0.001) but not in non-ME states (HR: 0.95, 95% CI: 0.80–1.12, p = 0.536). ConclusionME status consistently predicted increased utilization of care processes that improved ICC outcomes, including greater rates of curative-intent surgery and multimodal therapy.

Spatial immunophenotypes predict clinical outcome in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a severe malignant tumour that shows only modest responses to immunotherapy. We aimed to identify the spatial immunophenotypes of iCCA and delineate potential immune escape mechanisms. Multiplex immunohistochemistry (mIHC) was performed to quantitatively evaluate the distribution of 16 immune cell subsets in intratumour, invasive margin and peritumour areas in a cohort of 192 treatment-naïve patients with iCCA. Multiregion unsupervised clustering was used to determine three spatial immunophenotypes, and multiomics analyses were carried out to explore functional differences.Results: iCCA displayed a region-specific distribution of immune cell subsets with abundant CD15+ neutrophil infiltration in intratumour areas. Three spatial immunophenotypes encompassing inflamed (35%), excluded (35%) and ignored (30%) phenotypes were identified. The inflamed phenotype showed characteristics of abundant immune cell infiltration in intratumour areas, increased PD-L1 expression and relatively favourable overall survival. The excluded phenotype with a moderate prognosis was characterized by immune cell infiltration restricted to the invasive margin or peritumour areas and upregulation of activated hepatic stellate cells, extracellular matrix and Notch signalling pathways. The ignored phenotype, with scarce immune cell infiltration across all subregions, was associated with MAPK signalling pathway elevation and a poor prognosis. The excluded and ignored phenotypes, constituting non-inflamed phenotypes, shared features of an increased angiogenesis score, TGF-β and Wnt-β catenin pathway upregulation and were enriched for BAP1 mutations and FGFR2 fusions. We identified three spatial immunophenotypes with different overall prognoses in iCCA. Tailored therapies based on the distinct immune evasion mechanisms of the spatial immunophenotypes are needed. The contribution of immune cell infiltration in the invasive margin and peritumour areas has been proved. We explored the multiregional immune contexture of 192 patients to identify three spatial immunophenotypes in intrahepatic cholangiocarcinoma (iCCA). By integrating genomic and transcriptomic data, phenotype-specific biological behaviours and potential immune escape mechanisms were analysed. Our findings provide a rationale to develop personalized therapies for iCCA.

Impact of the Affordable Care Act on Presentation, Treatment, and Outcomes of Intrahepatic Cholangiocarcinoma

BackgroundThe Affordable Care Act (ACA) transformed the US healthcare system, expanding healthcare insurance coverage. However, its impact on rare malignancies that lack an established screening strategy such as intrahepatic cholangiocarcinoma (ICC) remains ill-defined. MethodsPatients diagnosed with ICC were identified from the National Cancer Database and divided relative to ACA implementation. Multivariate logistic regression analyses were performed to evaluate association with stage at diagnosis, receipt of surgical and multimodal treatments, and survival. ResultsAmong the 9095 patients, 5636 (62.0%) were diagnosed before and 3459 (38.0%) after the implementation of the ACA. Across US regions, rates of early-stage diagnosis increased in the post-ACA era (Northeast, 62.9% vs. 85.2%; South, 63.7% vs. 78.5%; Midwest, 62.1% vs. 83.4%; West, 55.5% vs. 75.4%; p < 0.001). On multivariate analyses, the post-ACA era was associated with increased early-stage diagnosis (OR = 2.19; 95% CI 1.79–2.69), and receipt of surgical treatment (OR = 1.19, 95% CI 1.03–1.38) (both p < 0.01). Furthermore, the ACA’s Medicaid expansion (ME) was also associated with improved overall survival (HR = 0.89, 95% CI 0.80–0.99, p = 0.038). Of note, although the odds of receiving surgical treatment increased after ACA for non-Hispanic White patients (OR = 1.34; 95% CI 1.20–1.49; p < 0.001), no such effect was observed in non-Hispanic Black (OR = 1.01, 95% CI 0.71–1.45), Hispanic (OR = 1.44, 95% CI 0.99–2.09), or others (OR = 1.43, 95% CI 0.98–2.10) (all p > 0.05). ConclusionsThe implementation of the ACA increased rates of early diagnosis and receipt of surgical treatment. Additionally, ME improved short- and long-term outcomes. However, racial and socioeconomic disparities persist, resulting in inequitable access to care and outcomes for patients with ICC.

Association between Immunohistochemistry Markers and Tumor Features and Their Diagnostic and Prognostic Values in Intrahepatic Cholangiocarcinoma.

This study investigated the expression of some frequently used immunohistochemistry (IHC) markers. Besides, we evaluated their correlations with the clinical features and outcomes of intrahepatic cholangiocarcinoma (ICC). Patients who underwent surgical removal of the ICC tumors were followed up for 4 years. The paraffin-embedded sections were used to obtain different markers, including CK7, CK19, CK20, CDX2, Glypican3, Hepa1, Ki-67, Villin, and SATB1. Overall survival in relation to IHC marker expression patterns and other clinical characteristics was evaluated by Kaplan-Meier survival curve and log-rank test, followed by the Cox proportional hazard model (to evaluate the relationship between multiple factors and the overall postoperative survival). A total of 122 ICC patients (67 males and 55 females, averagely aged 57.75) were included in this study. There were 44 cases with vascular invasion, 46 cases with lymphatic metastasis, and 13 cases with distant metastasis. CK7 was negatively correlated with lymphatic metastasis; and in distant-metastasis cases, the positive ratio of SATB1 was lower. Interestingly, SATB1 expression indicated a poorer survival, while Villin expression was associated with a better survival. The COX regression analysis showed that female was a protective factor versus male, Villin expression was a strong protective factor, and Ki-67 expression was correlated with a poor survival. Together, IHC markers are associated with tumor features and postoperative survival, especially for SATB1 as a risk factor and Villin as a protective marker, and female ICC patients may have better survival than males.

Impact of cirrhosis on long-term survival outcomes of patients with intrahepatic cholangiocarcinoma.

BackgroundThe correlation between cirrhosis and the long‐term oncological outcome in intrahepatic cholangiocarcinoma (ICC) is debatable, and this study aimed to explore the impact of cirrhosis on the long‐term prognosis of patients with ICC.MethodsA total of 398 ICC patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2018. The diagnosis of cirrhosis was based on the Ishak fibrosis score provided by the SEER database. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were performed to minimize the potential confounders. Overall survival (OS) and cancer‐specific survival (CSS) were observed, and the Cox regression model was used to select potential factors that affect the prognosis of the patients with ICC.ResultsOf the included patients, there were 142 patients and 256 patients in the cirrhotic and noncirrhotic groups, respectively. Additionally, 299 of 398 patients (75.1%) died following a median follow‐up of 19 months (interquartile range [IQR], 7, 43). The OS and CSS indicated advantage trend in the noncirrhotic group than the cirrhotic group in either the original cohort (OS: 17 vs 12 months, p = 0.023; CSS: 26 vs 15 months, p = 0.004) or the PSM (OS: 17 vs 12 months, p = 0.52; CSS: 22 vs 14 months, p = 0.15) or IPTW (OS: 20 vs 13 months, p = 0.163; CSS: 22 vs 15 months, p = 0.059) cohorts. Subgroup analyses displayed that the prognosis of patients who experienced surgery for ICC in the noncirrhotic group was better than that of the cirrhotic group with regard to OS and CSS.ConclusionsCollectively, it seems that the noncirrhotic patients have similar relative OS but better CSS compared with that of the cirrhotic patients.

Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker Predicting Oncological Outcome in Intrahepatic Cholangiocarcinoma

Introduction: The invasion of cancers cells to nerves and nerve fibers is a hallmark feature of intrahepatic cholangiocarcinoma (iCCA). The density of nerve fibers (NFs) in the tumor microenvironment (TME) has been investigated in some malignancies, however, its role in in iCCA remains to be elucidated.

Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma

The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TLSs in iCCA. We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples. A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts. The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs. Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. This bi-institutional study of patients with confirmed iCCA (n=412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P<0.0001), KRAS (P=0.0001), and CDKN2A (P<0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n=209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P=0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P<0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P<0.001]; regional lymph node metastases [P<0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P=0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2months; P<0.001), with high-risk genetic alterations alone (median OS, 38.6months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Investigating effects of preoperative inflammatory biomarkers on predicting survival outcomes of intrahepatic cholangiocarcinoma after curative resection

IntroductionIntrahepatic cholangiocarcinoma (ICC) stands as the second most common malignant tumor in the liver with poor patient prognosis. Increasing evidences have shown that inflammation plays a significant role in tumor progression, angiogenesis, and metastasis. However, the prognosis significance of inflammatory biomarkers on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is poorly recognized.MethodsICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII), were investigated.ResultsReceiver operating characteristic (ROC) curves showed no significance in NLR, PLR, and LMR in RFS and OS, while significant results were shown on SII in both RFS (P = 0.035) and OS (P = 0.034) with areas under ROC curve as 0.63 (95%CI 0.52–0.74) and 0.62 (95%CI 0.51–0.72), respectively. Kaplan-Meier curves revealed a statistically significant better survival data in SII-low groups on both RFS (P < 0.001) and OS (P < 0.001). The univariate and multivariate analyses revealed that higher level of SII was independently associated with both poorer RFS time and OS time. However, no significant result was shown on NLR, PLR, or LMR.ConclusionSII is an effective prognostic factor for predicting the prognosis of ICC patient undergone curative hepatectomy, while NLR, PLR, and LMR are not associated with clinical outcomes of these patients.

Recent progress in molecular targeted therapies for intrahepatic cholangiocarcinoma

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

Machine learning: an approach to preoperatively predict PD-1/PD-L1 expression and outcome in intrahepatic cholangiocarcinoma using MRI biomarkers

ObjectiveTo investigate the preoperative predictive value of non-invasive imaging biomarkers for programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) expression and outcome in intrahepatic cholangiocarcinoma (ICC) using machine learning.MethodsPD-1/PD-L1 expression in 98 ICC patients was assessed by immunohistochemistry, and their prognostic effects were analysed using Cox regression and Kaplan-Meier analysis. Radiomic features were extracted from MRI in the arterial and portal vein phases, and three sets of Radiomics score (Radscore) with good performance were derived respectively as biomarkers for predicting PD-1, PD-L1 expression and overall survival (OS). PD-1 and PD-L1 expression models were developed using the Radscore (arterial phase), clinico-radiological factors and clinical factors, individually and in combination. The imaging-based OS predictive model was constructed by combining independent predictors among clinico-radiological, clinical factors and OS Radscore. Pathology-based OS model using pathological and clinical factors was also constructed and compared with imaging-based OS model.ResultsThe highest area under the curves of the models predicting PD-1 and PD-L1 expression was 0.897 and 0.890, respectively. PD-1+ and PD-L1+ cases had worse outcomes than negative cases. The 5-year survival rates of PD-1+ and PD-1− cases were 12.5% and 48.3%, respectively (p<0.05), whereas the 5-year survival was 21.9% and 39.4% for PD-L1+ and PD-L1− cases, respectively (p<0.05). The imaging-based OS model involved predictors of clinico-radiological ‘imaging classification’, radiomics ‘Radscore’ from arterial phase and carcinoembryonic antigen (CEA) level (C-index:0.721). It performed better than pathology-based model (C-index: 0.698) constructed by PD-1/PD-L1 expression status and CEA level. The imaging-based OS model is potential for practice when the pathology assay is unavailable and could divide ICC patients into high-risk and low-risk groups, with 1-year, 3-year and 5-year survival rates of 57.1%, 14.3% and 12.4%, and 87.8%, 63.3% and 55.3%, respectively (p<0.001).ConclusionsMRI radiomics could derive promising and non-invasive biomarker in evaluating PD-1/PD-L1 expression and prognosis of ICC patients.

Surveillance for Hepatocellular Carcinoma Also Improves Survival of Incidentally Detected Intrahepatic Cholangiocarcinoma Arisen in Liver Cirrhosis

Background: Due to its poor survival, intrahepatic cholangiocarcinoma (ICC) is held to be a much more aggressive cancer than hepatocellular carcinoma (HCC). In most published series, patients were diagnosed when symptomatic. However, ICC is now increasingly being discovered during the surveillance for HCC in cirrhosis. Whether this earlier detection of ICC is associated with an equally dismal prognosis or not is unknown. Methods: This is amulticenter retrospective study of consecutive ICC patients. Patients were stratified into subgroups according to the absence/presence of cirrhosis. A propensity score matching was performed to reduce the potential biases. Cirrhotic patients were further stratified according to their surveillance status. The lead-time bias and its potential effects were also estimated. Results: We gathered 184 patients. Eighty-five patients (46.2%) were cirrhotic. Liver cirrhosis was not related to a worse overall survival (33.0 vs. 32.0 months, p = 0.800) even after the propensity score analysis (43.0 in vs. 44.0 months in 54 pairs of patients, p = 0.878). Among the cirrhotic population, 47 (55.3%) patients had received a diagnosis of ICC during a surveillance programme. The 2 subgroups differed in maximum tumour dimensions (30 vs. 48 mm in surveyed and non-surveyed patients, respectively). Surveyed patients were more likely to receive surgical treatments (59.8 vs. 28.9%, p = 0.003). Overall survival was higher in surveyed patients (51.0 vs. 21.0 months, p < 0.001). These benefits were confirmed after correcting for the lead-time bias. Conclusions: Cirrhotic patients have different clinical presentation and outcomes of ICC according to their surveillance status. In our series, ICC in cirrhosis was not associated with worse OS. Cirrhosis itself should not discourage either surgical or non-surgical treatments.

Impact of viral hepatitis B status on outcomes of intrahepatic cholangiocarcinoma: a meta-analysis

To estimate the impact of viral hepatitis B status on outcomes of intrahepatic cholangiocarcinoma. We searched Pubmed and Embase for original articles that evaluated the impact of hepatitis B virus infection on outcomes of intrahepatic cholangiocarcinoma. The present study was conducted to generate odd ratios (ORs) with 95% confidence intervals (CIs) for pre-identified prognostic factors, overall survival, and recurrence. From 438 studies, we identified eight articles that compared outcomes between hepatitis B virus-infected patients and the others. In terms of clinicopathological characteristics, patients in the hepatitis B virus group significantly demonstrated single nodular tumor (OR 0.7; 95% CI 0.5-0.9; p = 0.01), infrequent lymph node metastasis (OR 0.5; 95% CI 0.3-0.6; p < 0.01), and infrequent perineural infiltration (OR 0.3; 95% CI 0.2-0.8; p < 0.01). No significant between-group differences were found in tumor diameter, vascular invasion, and tumor differentiation. Previous or temporary infection (seropositivity for hepatitis B core antibody) revealed no significant impact on clinicopathological characteristics. For survival outcomes, meta-analysis demonstrated that hepatitis B virus group had significantly better overall survival, recurrence rate, and median survival (p < 0.01). Our results suggest that hepatitis B virus infection is a powerful predictor of favorable survival outcomes for intrahepatic cholangiocarcinoma and significantly affects clinicopathological characteristics. Viral hepatitis B status needs to be taken into account and then establish therapeutic approaches.

The effect of socioeconomic factors on the outcome of intrahepatic cholangiocarcinoma.

465 Background: To investigate the impact of socioeconomic factors on overall survival (OS) for patients with intrahepatic cholangiocarcinoma (ICC) at an inner-city tertiary care hospital. Methods: Consecutive patients treated for ICC diagnosed between 2005 and 2016 in the cancer registry were studied. Patients were stratified by demographic, socioeconomic variables, and treatment course. Kaplan-Meier curves and Cox proportional hazard modeling were performed. Results: Patients were 52% male (95 pts) and 74% white (136 pts) with mean age of 65.7 yrs (SD 10.7 yrs). 82% of patients were married or had been previously married (148 pts). 11% of patients had Medicaid as their primary insurance (20 pts), 45% of patients had Medicare (78 pts) and 44% of patients had private insurance (77 pts). Patients with private insurance (66 pts, 87%) and Medicare (64 pts, 83%) were more likely to have been married than Medicaid (12 pts, 60%) (p = 0.036). Patients with Medicare (mean 72.0 yrs, SD 6.9 yrs) were older than private insurance patients (mean 60.3 yrs, SD 10.3 yrs) and Medicaid patients (mean 61.8 yrs, SD 12.4 yrs) (p &lt; 0.001). Gender and ethnicity were similarly distributed by primary insurance. Median OS stratified by primary insurance demonstrated median OS in private insurance of 13.2 mo (95% CI: 8.2–18.7 mo) vs 7.3 mo (95% CI: 3.8–10.6 mo) for Medicare (HR 1.3, p = 0.11) vs 4.7 mo (95% CI: 1.7–11.3 mo) for Medicaid (HR 1.8, p = 0.0488), (p = 0.0465). Cancer-directed treatments were utilized by 81% in private insurance vs. 67% in Medicare vs 67% in Medicaid (p = 0.18). Median OS stratified by main treatment demonstrated 43.3 mo in resection (37 pts, 21%), 17.3 mo in locoregional therapy (LRT) (22 pts, 13%), 10.0 mo in chemotherapy or radiation (79 pts, 45%), and 1.4 mo in palliative or no treatment (37 pts, 21%) (p &lt; 0.0001). Increased age was associated with decreased median OS (correlation -0.23, p = 0.0019). No differences in median OS were seen with ethnicity, gender, or marital status. Conclusions: Screening and early treatments appear to affect the OS of patients with ICC. Further investigations for preventive care for vulnerable populations to enhance survivals are warranted.

Expression of VEGFR-3 in intrahepatic cholangiocarcinoma correlates with unfavorable prognosis through lymphangiogenesis.

Background & aims: VEGFR-3 has been shown of great significance in lymph node metastasis and some malignancies, however, its expression in tumors and impact on outcome of intrahepatic cholangiocarcinoma (iCCA) remains unknown. The aim of this study was to assess the role of VEGFR-3 positive tumors for prognosis of iCCA and tumor-associated lymphangiogenesis.Methods: Clinicopathological features, prognostic factors and survival rate were analyzed to evaluate the influence of VEGFR-3 positive expression on prognosis of iCCA. In addition, tumor-associated lymphangiogenesis quantified as micro-lymphatic vessel density (MLVD) was assessed to explore the correlation between VEGFR-3 expression and lymph node metastasis for iCCA.Results: Patients with VEGFR-3 positive tumors had increased lymph node metastasis (p=0.025) and were more likely to suffer from tumor recurrence compared with VEGFR-3 negative tumors (p<0.001). VEGFR-3 expression in tumors was identified as an independent prognostic factor for both overall and recurrence-free survival in surgical resected patients with iCCA. In addition, higher MLVD was significantly associated with VEGFR-3 positive expression in tumors (p<0.001), which facilitate lymph node metastasis and significantly worse survival rates.Conclusions: Our study reveals that VEGFR-3 positive expression in tumors represents an independent prognostic factor for both overall and recurrence-free survival in hepatic resected patients with iCCA. VEGFR-3 positive tumors favor lymph node metastasis, tumor recurrence and worse outcomes through tumor-associated lymphangiogenesis.

Research progresses of primary liver cancer from 2017 annual meeting of Chinese Society of Clinical Oncology

In the twentieth session of the National Clinical Oncology Conference and 2017 annual meeting of Chinese Society of Clinical Oncology (CSCO), many progre-ssions have been made in the diagnosis and treatment of primary liver cancer. (1) A preliminary report of the real world study of primary liver cancer in China was released. (2) Emerging diagnostic techniques and predictive models can detect preoperative liver cirrhosis and risk of postoperative liver failure in patients with hepatocellular carcinoma (HCC). (3) Photodynamic diagnostic technology can ensure histological clearance with nega-tive surgical margin and preserve as much liver parenchyma as possible. (4) Lenvatinib is expected to be the first-line targeted drug for the treatment of patients with unresectable HCC following sorafenib. (5) Immunotherapy with Nivolumab and Pembro-lizumab is still a hot topic in the field of HCC management. (6) Though a vast heterogeneity of patterns of liver resection for HCC exists between two large centers from the East and the West, their surgical safety and long-term efficacy are actually comparable. (7) Routine lymphadenectomy, active surgical intervention for patients with late-stage tumors, ensuring the negative margins of resection and comprehensive treatment of postoperative recurrence are expected to improve the long-term outcomes of intrahepatic cholangiocarcinoma (ICC). Key words: Liver neoplasms, primary; Sorafenib; Lenvatinib; Targeted therapy; Immunotherapy