The association of carbohydrate antigen 19-9 response with radiologic response and survival in intrahepatic cholangiocarcinoma: A prospective cohort study.

BACKGROUND: The role of carbohydrate antigen 19-9 (CA 19-9) in response assessment among patients with intrahepatic cholangiocarcinoma (iCCA) remains unknown. The authors studied the association of the CA 19-9 response (defined as a reduction >50% from baseline) with the radiologic response and the outcome in patients with unresectable iCCA. METHODS: A prospective cohort of 422 patients who were initially diagnosed with unresectable iCCA, had baseline CA 19-9 levels ≥100 U/mL, and received treatment with systemic therapies at the authors' institution between January 2017 and December 2021 were enrolled in this study. The radiologic response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A landmark assessment of the CA 19-9 response and the radiologic response was performed. The associations between CA 19-9 response and imaging response, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Two hundred sixty-seven patients (63.3%) had a CA 19-9 response. A CA 19-9 response was observed in 123 of 132 (93.2%) radiologic responders and in 144 of 290 (49.7%) radiologic nonresponders (p < .001). CA 19-9 responders outperformed nonresponders in median PFS (10.6 vs. 3.6 months; hazard ratio [HR], 4.8 months; 95% confidence interval [CI], 3.8-6.0 months; p < .001) and OS (21.4 vs. 6.3 months; HR, 5.3 months; 95% CI, 4.2-6.7 months; p < .001). The common independent predictors of both OS and PFS included metastasis, CA 19-9 nonresponder status, and radiologic nonresponder status in multivariable analysis. CONCLUSIONS: CA 19-9 response is a valuable addition to assess tumor response and is associated with improved outcomes in patients with iCCA. Achieving a CA 19-9 response should be one of the therapeutic objectives of patients with iCCA after systemic therapies. PLAIN LANGUAGE SUMMARY: A decline in carbohydrate antigen 19-9 levels from elevated baseline levels should be one of the therapeutic aims of patients with intrahepatic cholangiocarcinoma who are managed with systemic therapies.

MYC determines lineage commitment in KRAS-driven primary liver cancer development.

BACKGROUND & AIMS: Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their tumour biology and responses to cancer therapies. Liver cells harbour a high degree of cellular plasticity and can give rise to either HCC or iCCA. However, little is known about the cell-intrinsic mechanisms directing an oncogenically transformed liver cell to either HCC or iCCA. The scope of this study was to identify cell-intrinsic factors determining lineage commitment in PLC. METHODS: Cross-species transcriptomic and epigenetic profiling was applied to murine HCCs and iCCAs and to two human PLC cohorts. Integrative data analysis comprised epigenetic Landscape In Silico deletion Analysis (LISA) of transcriptomic data and Hypergeometric Optimization of Motif EnRichment (HOMER) analysis of chromatin accessibility data. Identified candidate genes were subjected to functional genetic testing in non-germline genetically engineered PLC mouse models (shRNAmir knockdown or overexpression of full-length cDNAs). RESULTS: Integrative bioinformatic analyses of transcriptomic and epigenetic data pinpointed the Forkhead-family transcription factors FOXA1 and FOXA2 as MYC-dependent determination factors of the HCC lineage. Conversely, the ETS family transcription factor ETS1 was identified as a determinant of the iCCA lineage, which was found to be suppressed by MYC during HCC development. Strikingly, shRNA-mediated suppression of FOXA1 and FOXA2 with concomitant ETS1 expression fully switched HCC to iCCA development in PLC mouse models. CONCLUSIONS: The herein reported data establish MYC as a key determinant of lineage commitment in PLC and provide a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. IMPACT AND IMPLICATIONS: Liver cancer is a major health problem and comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), two frequent and lethal tumour types that differ regarding their morphology, tumour biology, and responses to cancer therapies. We identified the transcription factor and oncogenic master regulator MYC as a switch between HCC and iCCA development. When MYC levels are high at the time point when a hepatocyte becomes a tumour cell, an HCC is growing out. Conversely, if MYC levels are low at this time point, the result is the outgrowth of an iCCA. Our study provides a molecular explanation why common liver-damaging risk factors such as alcoholic or non-alcoholic steatohepatitis can lead to either HCC or iCCA. Furthermore, our data harbour potential for the development of better PLC therapies.

Intrahepatic Cholangiocarcinoma: State of the Art of FGFR Inhibitors.

OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA), the second most common type of primary liver tumor, has an increasing incidence in the past few decades. iCCA is highly malignant, with a 5-year survival rate of approximately 5-10%. Surgical resection is usually the prescribed treatment for patients with early stage iCCA; however, patients are usually in an advanced stage iCCA upon diagnosis. Currently, targeted therapy combined with chemotherapy and other comprehensive treatment measures have been mainly adopted as palliative treatment measures. As a common candidate of targeted therapy, FGFR inhibitors have demonstrated their unique advantages in clinical trials. At present, the prospect of FGFR targeted therapy is encouraging. The landscape of FGFR inhibitors in iCCA is needed to be showed urgently. METHODS: We searched relative reports of clinical trials on FGFR inhibitors in PubMed as well as Web of Science. We also concluded other available clinical trials of FGFR inhibitors (Data were collected from clinicaltrials.gov). RESULTS: Several relatively effective targeted drugs are being used in clinical trials. Some preliminary results indicate the outlook of targeted therapy such as BGJ398, TAS120, and HSP90 inhibitors. CONCLUSIONS: In summary, FGFR targeted therapy has broad prospects for the treatment of iCCA.

The role of ALPPS in intrahepatic cholangiocarcinoma.

PURPOSE: Surgical resection constitutes the mainstay of curative treatment for intrahepatic cholangiocarcinoma (iCCA). Complete tumor clearance can only be achieved with extended liver resections and as such, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may facilitate surgical resectability. The present study aims to evaluate the technical feasibility and oncologic outcome of ALPPS in iCCA. METHODS: A set of 14 patients who underwent ALPPS in a single center between 2011 and 2017 were statistically analyzed for perioperative and oncologic outcome. RESULTS: Of all patients undergoing stage 1 of ALPPS, 12 (86%) patients were subsequently completed in stage 2 surgery. Patients who completed the ALPPS procedure showed a median overall survival (OS) of 4.2 years and a 3-year survival of 64%. Individuals without lymphatic metastases (n = 7) were all alive 1 year after surgery and if deceased, they died more than 4 years after surgery, while no patient with lymphatic metastases (n = 5) was alive 1 year after surgery. CONCLUSION: This is the largest single-center experience of ALPPS in iCCA currently available in the literature showing excellent technical feasibility and encouraging overall survival in these patients.

Epidemiology, survival and new treatment modalities for intrahepatic cholangiocarcinoma.

Background: Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with increasing incidence and poor survival rates. This study aims to evaluate the incidence and survival trends of iCCA patients over 20 years using a national cancer database, and assess the temporal association between survival and landmark clinical trials. Methods: Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rates (AAIRs) were calculated from 2000 to 2020. Overall survival was analyzed based on diagnosis time and disease stage. Subgroup analysis was performed for patients diagnosed between 2015 and 2020. Landmark clinical trials were reviewed to determine temporal changes in survival. Results: In this analysis of 28,918 iCCA patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 [annual percent change (APC) 6.94, 95% confidence interval (CI): 6.32 to 7.56], with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted median overall survival (mOS) improved from 5.28 months in 2000 to 9.3 months in 2013, then stabilized between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 months in 2000-2010 to 9.06 months in 2010-2020. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3, 12.1, and 5.4 months for local, regional, and distant stages, respectively. Conclusions: The study indicates a steady rise in iCCA incidence since 2000 across all subgroups. Survival rates improved since 2000 but stabilized after 2013, following the ABC-02 trial publication in 2010. The impact of more recent clinical trials on survival rates requires further analysis in the coming years.

Real-world outcomes of chemotherapy plus immune checkpoint inhibitors versus chemotherapy alone in advanced, unresectable, and recurrent intrahepatic cholangiocarcinoma.

Background: There are limited treatment options available to improve the prognosis of patients with advanced or metastatic cholangiocarcinoma particularly intrahepatic cholangiocarcinoma (iCCA). This study aimed to evaluate the efficacy and safety of combining chemotherapy plus anti-PD-1/L1 drugs compared to chemotherapy alone in advanced, unresectable, and recurrent intrahepatic cholangiocarcinoma patients. Methods: Patients with advanced, unresectable, or recurrent iCCA who received chemotherapy combined with PD-1/PD-L1 inhibitors or chemotherapy alone were retrospectively screened and analyzed. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcomes were overall response rate (ORR), disease control rate (DCR), and safety. Results: 81 eligible patients were included in the study (chemotherapy plus anti-PD-1/L1 group n=51, and chemotherapy-alone group n=30). The median OS was 11 months for the chemotherapy plus anti-PD-1/L1 group, significantly longer than the 8 months in the chemotherapy-alone group, with a hazard ratio (HR) of 0.53 (95% CI 0.30-0.94, P = 0.008). The median PFS of 7 months in the chemotherapy plus anti-PD-1/L1 group was significantly longer than the 4 months in the chemotherapy-alone group, with HR of 0.48 (95% CI 0.27-0.87); P = 0.002). Similarly, the combined therapy group showed a higher ORR (29.4%) and DCR (78.4%) compared to 13.3% and 73.3% in the chemotherapy-alone group, respectively. More grade 3-4 treatment-related adverse effects were recorded in the chemotherapy plus anti-PD-1/L1 group (66.7%) compared to the chemotherapy-alone group (23.3%), however, they were manageable and tolerable. Conclusion: Chemotherapy plus anti-PD-1/L1 represents a more effective and tolerable treatment option for advanced, unresectable, and recurrent iCCA patients compared to chemotherapy alone.

Cholangiocarcinoma: The Current Status of Surgical Options including Liver Transplantation.

Cholangiocarcinoma (CCA) poses a substantial threat as it ranks as the second most prevalent primary liver tumor. The documented annual rise in intrahepatic CCA (iCCA) incidence in the United States is concerning, indicating its growing impact. Moreover, the five-year survival rate after tumor resection is only 25%, given that tumor recurrence is the leading cause of death in 53-79% of patients. Pre-operative assessments for iCCA focus on pinpointing tumor location, biliary tract involvement, vascular encasements, and metastasis detection. Numerous studies have revealed that portal vein embolization (PVE) is linked to enhanced survival rates, improved liver synthetic functions, and decreased overall mortality. The challenge in achieving clear resection margins contributes to the notable recurrence rate of iCCA, affecting approximately two-thirds of cases within one year, and results in a median survival of less than 12 months for recurrent cases. Nearly 50% of patients initially considered eligible for surgical resection in iCCA cases are ultimately deemed ineligible during surgical exploration. Therefore, staging laparoscopy has been proposed to reduce unnecessary laparotomy. Eligibility for orthotopic liver transplantation (OLT) requires certain criteria to be granted. OLT offers survival advantages for early-detected unresectable iCCA; it can be combined with other treatments, such as radiofrequency ablation and transarterial chemoembolization, in specific cases. We aim to comprehensively describe the surgical strategies available for treating CCA, including the preoperative measures and interventions, alongside the current options regarding liver resection and OLT.

Diagnostic value of carbohydrate antigen 50 in biliary tract cancer: A large-scale multicenter study.

BACKGROUND: To date, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have been widely used for the screening, diagnosis and prediction of biliary tract cancer (BTC) patients. However, few studies with large sample sizes of carbohydrate antigen 50 (CA50) were reported in BTC patients. METHODS: A total of 1121 patients from the Liver Cancer Clin-Bio Databank of Anhui Hepatobiliary Surgery Union between January 2017 and December 2022 were included in this study (673 in the training cohort and 448 in the validation cohort): among them, 458 with BTC, 178 with hepatocellular carcinoma (HCC), 23 with combined hepatocellular-cholangiocarcinoma, and 462 with nontumor patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the diagnostic efficacy and clinical usefulness. RESULTS: ROC curves obtained by combining CA50, CA19-9, and AFP showed that the AUC value of the diagnostic MODEL 1 was 0.885 (95% CI 0.856-0.885, specificity 70.3%, and sensitivity 84.0%) in the training cohort and 0.879 (0.841-0.917, 76.7%, and 84.3%) in the validation cohort. In addition, comparing iCCA and HCC (235 in the training cohort, 157 in the validation cohort), the AUC values of the diagnostic MODEL 2 were 0.893 (95% CI 0.853-0.933, specificity 96%, and sensitivity 68.6%) in the training cohort and 0.872 (95% CI 0.818-0.927, 94.2%, and 64.6%) in the validation cohort. CONCLUSION: The model combining CA50, CA19-9, and AFP not only has good diagnostic value for BTC but also has good diagnostic value for distinguishing iCCA and HCC.

Narrative review: current management and novel targeted therapies in intrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is a rare hepatic malignancy with poor prognosis, which has seen an increased incidence over the last decade. Most patients present with advanced disease that is not amenable to surgical resection, and those who are able to undergo resection, frequently develop recurrent disease. With the rise of precision medicine, several targetable mutations have been described for iCCA and are currently under investigations. The development of improved targeted therapies is critical to prolonged overall survival (OS), and the use of targeted agents for iCCA is currently the focus of several ongoing randomized controlled trials. The objective of this review is to summarize current guidelines for diagnosis, surgical resection, and systemic treatment, which includes ongoing clinical trials investigated targeted therapies. METHODS: A comprehensive review was performed using MEDLINE/PubMed with the end search date of October 1, 2022. In PubMed the terms "intrahepatic cholangiocarcinoma," "bile duct cancer", "targeted therapies", and "clinical trials" were searched. KEY CONTENT AND FINDINGS: The mainstay of treatment for iCCA is R0 resection with lymphadenectomy. Following surgical resection, new guidelines recommend 6 months of adjuvant capecitabine. Among patients with advanced or metastatic disease, systemic chemotherapy plays a significant role in prolonging survival for these patients. CONCLUSIONS: Surgical resection represents the mainstay of treatment followed by 6 months of adjuvant capecitabine. While additional data is needed through randomized controlled trials, targeted therapies including fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), and erythroblastic oncogene B2 (ErbB2) inhibitors offer promising results as adjuncts to current standard of care in iCCA, particularly among individuals with unresectable disease. Future recommendations regarding the use of targeted therapy will emerge as clinical trial data become available.

HMGA1 augments palbociclib efficacy via PI3K/mTOR signaling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer that is challenging to diagnose at an early stage. Despite recent advances in combination chemotherapy, drug resistance limits the therapeutic value of this regimen. iCCA reportedly harbors high HMGA1 expression and pathway alterations, especially hyperactivation of the CCND1/CDK4/CDK6 and PI3K signaling pathway. In this study, we explored the potential of targeting CDK4/6 and PI3K inhibition to treat iCCA. METHODS: The significance of HMGA1 in iCCA was investigated with in vitro/vivo experiments. Western blot, qPCR, dual-luciferase reporter and immunofluorescence assays were performed to examine the mechanism of HMGA1 induced CCND1 expression. CCK-8, western blot, transwell, 3D sphere formation and colony formation assays were conducted to predict the potential role of CDK4/6 inhibitors PI3K/mTOR inhibitors in iCCA treatment. Xenograft mouse models were also used to determine the efficacy of combination treatment strategies related to HMGA1 in iCCA. RESULTS: HMGA1 promoted the proliferation, epithelial-mesenchymaltransition (EMT), metastasis and stemness of iCCA. In vitro studies showed that HMGA1 induced CCND1 expression via promoting CCND1 transcription and activating the PI3K signaling pathway. Palbociclib(CDK4/6 inhibitor) could suppress iCCA proliferation, migration and invasion, especially during the first 3 days. Although there was more stable attenuation of growth in the HIBEpic model, we observed substantial outgrowth in each hepatobiliary cancer cell model. PF-04691502(PI3K/mTOR inhibitor) exhibited similar effects to palbociclib. Compared with monotherapy, the combination retained effective inhibition for iCCA through the more potent and steady inhibition of CCND1, CDK4/6 and PI3K pathway. Furthermore, more significant inhibition of the common downstream signaling pathways is observed with the combination compared to monotherapy. CONCLUSIONS: Our study reveals the potential therapeutic role of dual inhibition of CDK4/6 and PI3K/mTOR pathways in iCCA, and proposes a new paradigm for the clinical treatment of iCCA.

A narrative review of intrahepatic cholangiocarcinoma: a surgical curative option.

BACKGROUND AND OBJECTIVE: Cholangiocarcinoma (CCA) is the second commonest primary liver malignancy. Nowadays, the only available treatment with curative intent of intrahepatic cholangiocarcinoma (iCCA) is surgical resection, with a 5-year overall survival (OS) of 25-40%. However, recurrence rate remains high. In this comprehensive review, we describe the newest surgical strategies for iCCA management, including vascular resection, the role of mini-invasive surgery, liver transplant, strategies for future liver remnant augmentation, and the role of neoadjuvant therapies. METHODS: A review of medical databases (PubMed, Scopus and Cochrane Database) was conducted selecting most relevant articles in English language without a specific timeframe. KEY CONTENT AND FINDINGS: Multifocal presentation, vascular, perineural invasion, and lymph nodes involvement are associated with poor outcome. Prognostic factors are being investigated to improve therapeutic approach and outcomes. The role of lymph nodes dissection remains debated. Harvesting at least 6 lymph nodes is recommended to ensure accurate nodal staging. Liver transplantation (LT) recently represented a treatment option only in patients with unresectable early disease (≤2 cm). CONCLUSIONS: Surgical resection remains the only potentially curative treatment for patients with CCA, but continue understanding in diagnosis, operative technique and chemotherapies are changing the landscape in the prognosis. Multicentric and randomized studies are necessaries in the future research with the intent to personalize the treatments, improve patient selection for the resection and reduce recurrence rate.

Laparoscopic versus open liver resection for intrahepatic cholangiocarcinoma: a systematic review of propensity score-matched studies.

Outcomes of laparoscopic liver resection (LLR) versus open LR (OLR) for intrahepatic cholangiocarcinoma (ICCA) are heterogeneous. We aimed to compare LLR and OLR for ICCA based on propensity-score-matched (PSM) studies. Two reviewers independently searched the online databases (PubMed, Embase, and Cochrane Library) for PSM studies that compared LLR and OLR for ICCA. The Ottawa-Newcastle Quality Assessment Scale with a cutoff of ≥ 7 was used to define higher-quality literature. Only 'high-quality' PSM analyses of the English language that met all our inclusion criteria were considered. A total of ten PSM trials were included in the analyses. Compared with OLR, although the lymph node dissection (LND) (RR = 0.67) and major hepatectomy rates were lower in the LLR group (RR = 0.87), higher R0 resections (RR = 1.05) and lower major complications (Clavien-Dindo grade ≥ III) (RR = 0.72) were also observed in the LLR group. In addition, patients in the LLR group showed less estimated blood loss (MD = - 185.52 ml) and shorter hospital stays as well (MD = - 2.75 days). Further analysis found the overall survival (OS) (HR = 0.91), disease-free survival (DFS) (HR = 0.95), and recurrence-free survival (HR = 0.80) for patients with ICCA after LLR were all comparable to those of OLR. LLR for selected ICCA patients may be technically safe and feasible, providing short-term benefits and achieving oncological efficacy without compromising the long-term survival of the patients.

Distinct sulfated glycans expressed in intrahepatic cholangiocarcinoma: a potential target for new therapy.

Cholangiocytes exhibit morphological and functional heterogeneity, depending on their anatomical localization; however, like other ductal organs, their mucosal surface is covered with mucin, which functions to prevent the entry of foreign substances, lubricate and prevent clogging by bile. Recently, the authors discovered that distinct sulfated glycans recognized by a series of antisulfated glycan antibodies are expressed not only in normal intrahepatic bile ducts but also in intrahepatic cholangiocarcinoma (iCCA). In this review, the authors first describe the anatomy of bile ducts and the biochemical characteristics of bile-duct-associated mucins, and then describe differences in structure and expression patterns of these sulfated glycans in physiological and pathological conditions. Finally, potential therapeutic strategies for iCCA using antisulfated glycan antibodies are discussed.

Paclitaxel Restores Sensitivity to Chemotherapy in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma.

The treatment of unresectable cholangiocarcinoma (CCA) is limited by the development of resistance to conventional first-line chemotherapy based on gemcitabine (GEM). In addition, a prior treatment with GEM frequently induces cross-resistance to other drugs employed in the second-line. Paclitaxel (PTX) is now emerging as an alternative option for the management of advanced/metastatic CCA. In the present work, we evaluate the antitumor activity of PTX in preclinical models of multidrug-resistant intrahepatic cholangiocarcinoma (iCCA). In vitro, PTX decreases tumor cell viability by affecting the cell cycle and inducing apoptosis and impairs the stem cell compartment. In vivo, a therapeutic regimen containing albumin-bound nanoparticle (Nab)-PTX overcomes drug resistance resulting in delayed tumor growth, impaired organization of the tumor vasculature, and reduced glucose uptake. Together, our results provide a rationale to consider PTX-based regimens in patients with iCCA who became refractory to conventional therapies.

Case report: immunotherapy successfully treated brain metastasis in intrahepatic cholangiocarcinoma and literature review.

Brain metastasis from intrahepatic cholangiocarcinoma (iCCA) is extremely rare, and no standard therapeutic strategy has been established. Camrelizumab is a programmed cell death protein 1 (PD-1) inhibitor that has been widely studied in treating liver cancer. Combined immunotherapy and targeted therapy are a promising approach for treating advanced iCCA. Despite that immune checkpoint inhibitor (ICI)-based neoadjuvant therapy on iCCA has shown a significant response rate and resection rate, few reports have shown the therapeutic efficacy of immunotherapy in treating brain metastasis from iCCA. Although PD-1 inhibitors such as pembrolizumab, nivolumab, or camrelizumab are increasingly applied in clinic practice to treat multiple malignancies, to the best of our knowledge, we report the first case of an iCCA patient with brain metastasis successfully treated with a combined immunotherapy and targeted therapy. The patient is a 54-year-old man with metastatic iCCA in brain treated though camrelizumab plus lenvatinib therapy with a complete response (CR). By the time of writing, he has had a progression-free survival of 17.5 months and did not experience any severe side effects related to this therapy. Camrelizumab plus lenvatinib therapy showed favorable efficacy and manageable toxicity for this patient with advanced iCCA and could be of interest for more prospective randomized trials to further verify the potential clinical benefits.

Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma progression and therapeutic resistance.

Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell type in the tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA), where they are actively involved in cancer progression through a complex network of interactions with other stromal cells. The majority of the studies investigating CAFs in iCCA have focused their attention on CAF tumor-promoting roles, remarking their potential as therapeutic targets. However, indiscriminate targeting of CAFs in other desmoplastic tumors has ended in failure with no effects or even accelerated cancer progression and reduced survival, indicating the urgent need to better understand the nuances and functions of CAFs to avoid deleterious effects. Indeed, recent single cell RNA sequencing studies have shown that heterogeneous CAF subpopulations coexist in the same tumor, some promoting- and other restricting- tumor growth. Moreover, recent studies have shown that in iCCA, diverse CAF subtypes interact differently with the cells of the TME, suggesting that CAFs may dynamically change their phenotypes during tumor progression, a field that remains uninvestigated. The characterization of heterogenous CAF subpopulations and their functionality, will provide a feasible and safer approach to facilitate the development of new therapeutic approaches aimed at targeting CAFs and their interactions with other stromal cells in the TME rather than solely tumor cells in iCCA. Here, we discuss the origin of CAFs, as well as their heterogeneity, plasticity, mechanisms and targeting strategies to provide a brief snapshot of the current knowledge in iCCA.

High expression of CCDC6 in relation to unfavorable outcome and immune cells infiltration in hepatobiliary carcinoma.

Background: The diagnosis of hepatobiliary carcinoma includes both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the first and the second most common hepatobiliary malignancies, respectively. CCDC6 (coiled-coil domain-containing protein 6) is a protein that interacts with apoptosis and DNA damage response elements and is commonly detected in cells. The prognostic and biological roles of CCDC6 in hepatobiliary carcinoma remain unknown. Methods: We used data from UALCAN, GEPIA, TIMER, GeneMANIA, STRING and HPA databases to determine the prognostic values and biological functions of CCDC6 in HCC and CCA. We downloaded the original online data from TCGA and GEO databases and analyzed them with R 3.2.2. We also gathered clinical records from patients with HCC (n = 94) and iCCA (n = 99) in our hospital to explore associations between CCDC6 expression and hepatobiliary carcinoma using immunohistochemistry detection. We used KEGG, GO and GESA analyses to explore relative pathways of CCDC6 in HCC and CCA. In addition, we assessed correlations between CCDC6 expression and tumor-infiltrating immune cells using data from the TIMER and GEPIA databases. Finally, we assessed associations between CCDC6 and marker genes of tumor-infiltrated immune cells in HCC to confirm some of our findings. Results: The mRNA and protein expressions of CCDC6 were noticeably upregulated in HCC and CCA tissues as compared with the expressions in healthy control tissues. The high CCDC6 expression levels were significantly correlated with advanced tumor grades as well as poor prognosis in patients with HCC, but not in patients with CCA. Our functional enrichment analysis revealed that CCDC6 is mainly involved in cell cycle processes, gene transcription, and immune cell-related pathways. Moreover, we found that the CCDC6 levels were positively correlated with the presence of tumor-infiltrating immune cells, including macrophages, CD4+T cells and dendritic cells. Conclusion: CCDC6 expression was increased in hepatobiliary carcinoma tissues. High expressions of CCDC6 were significantly associated with clinical severity variables (especially with advanced cancer stages and pathological tumor grades) and poor prognoses in patients with HCC. CCDC6 upregulation is associated with histone acetylation and immune infiltration in hepatobiliary carcinoma. In addition, CCDC6 has the potential to be used as a predictive biomarker during targeting therapy and immunotherapy.

PD-1 Inhibitors Plus Capecitabine as Maintenance Therapy for Advanced Intrahepatic Cholangiocarcinoma: A Case Report and Review of Literature.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with a poor prognosis. Recently, an immunotherapy strategy represented by programmed cell death 1 (PD-1) inhibitors has been applied to the systemic treatment of advanced iCCA. However, immunotherapy combined with chemotherapy as first-line maintenance therapy was rarely reported. Our report presented an advanced iCCA patient who had a dramatic response to the PD-1 inhibitor sintilimab combined with gemcitabine plus cisplatin as the first-line therapy and sintilimab combined with capecitabine as maintenance therapy, yielding an ongoing progression-free survival of 16 months.

Liver Transplantation for Intrahepatic Cholangiocarcinoma: What Are New Insights and What Should We Follow?

Intrahepatic cholangiocarcinoma (iCCA) is a complex malignancy carrying poor prognosis. Liver transplantation (LT) was historically contraindicated for iCCA, due to poor outcomes after LT. However, an increasing number of studies have challenged this premise, because LT alone or combined with neoadjuvant chemotherapy has achieved relatively satisfactory transplant outcomes in well selected iCCA cases. This current review based on existing clinical researches, evinced that LT might serve as a viable option in iCCA cases as follows: ① unresectable tumor restricted to 2 cm, along with context of chronic liver diseases; and ② unresectable tumor locally advanced within the liver (without extrahepatic metastasis or vascular invasion) but responses to tumor down-staging treatments (namely, systemic neoadjuvant therapy and/or locoregional therapy). On the contrary, it is recommended as contraindications in iCCA cases as follows: ① patients with tumor progression while waiting for a transplant (increase of diameter, macrovascular invasion, new nodules, escalation of carbohydrate antigen 19-9, or extrahepatic spread); ② patients with iCCA recurrence. Conclusively, tumor burden, tumor biology, and response to down-staging strategies should be taken into consideration before LT. Whereas, the concept of "locally advanced stage" remains to be defined in the future, especially the optimized combination of "maximum size of largest lesion", "number of lesions", with/without "tumor differentiation", just like the Milan criteria which is widely used for hepatocellular carcinoma. Given the scarcity of donor organ, and also the debate about LT in iCCA, accurate consensus about LT for iCCA patients is still urgently warranted.

Hepatocellular carcinoma (HCC) versus non-HCC: accuracy and reliability of Liver Imaging Reporting and Data System v2018.

PURPOSE: The Liver Imaging Reporting and Data System (LI-RADS) was created to standardize the diagnostic criteria for hepatocellular carcinoma (HCC) and has undergone multiple revisions including a recent update in 2018 (v2018). The primary aim of this study was to determine the diagnostic performance and interrater reliability (IRR) of LI-RADS v2018 for distinguishing HCC from non-HCC primary hepatic malignancy in patients 'at-risk' for HCC. A secondary aim was to assess the impact of changes introduced in the v2018 diagnostic algorithm. METHODS: This retrospective study combined a 10-year experience of pathologically proven primary liver malignancies from two large liver transplant centers. Two blinded readers independently evaluated each lesion and assigned a LI-RADS diagnostic category, additionally scoring all relevant imaging features. Changes in category based on the reader-provided features and the new v2018 criteria were assessed by a study coordinator. RESULTS: The final study cohort comprised 105 HCCs and 73 non-HCC primarily liver malignancies. LI-RADS had a high specificity for distinguishing HCC from non-HCC (89% and 90% for reader 1 and reader 2, respectively), and IRR was moderate to substantial for final LI-RADS category and most features. Revision of the LI-RADS v2018 diagnostic algorithm resulted in very few changes [5 (2.8%) and 3 (1.7%) for reader 1 and reader 2, respectively] in overall lesion classification. CONCLUSION: LI-RADS diagnostic categories and features had moderate to substantial IRR and high specificity for distinguishing HCC from non-HCC primary liver malignancy. Revision of LI-RADS v2018 diagnostic algorithm resulted in reclassification of very few lesions.