Radiation-based local-regional therapies for hepatocellular carcinoma (HCC) have gained wide acceptance due to promising rates of tumor response, survival, and safety profiles. After treatment, it is important to assess tumor response to determine further management, patient prognosis, and endpoint outcomes for clinical trials. To standardize imaging interpretation and reporting of HCC response to local-regional treatment, a few imaging-based response assessment systems were developed. Two of them have emerged as the most used: the Liver Imaging Reporting and Data System (LI-RADS) Treatment Response Algorithm (LR-TRA) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST). While these systems have been validated for the assessment of response to ablative locoregional therapies, assessment of response to radiation-based therapies can be challenged by persistent or evolving imaging features and is still an area of active research. Following the advances in technology and a better understanding of tumor biology that allowed for the increased application of radiation-based local-regional therapies for the treatment of HCC, research is still needed to address the limitations of current imaging criteria for assessing tumor response to these novel techniques. In this review, we describe radiation-based liver-directed treatment options, examine imaging criteria for assessing treatment response, discuss practical limitations and gaps in knowledge when applying these response criteria, and address future directions that may help to improve accuracy and outcomes when assessing response to radiation-based HCC treatment.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with a poor prognosis and high recurrence rate. Liver cancer stem cells (LCSCs), a small subset of HCC cells, have the capacity for self-renewal and the property of treatment resistance, suggesting that LCSCs are key factors in causing poor prognosis for HCC patients. In addition, LCSCs interact with immune cells to participate in the formation of an immunosuppressive microenvironment and escape the immune surveillance in HCC, especially lymphocytes. At present, immunotherapies for HCC are mainly based on reactivating the lymphocyte system, including immune checkpoint inhibitors, multifunctional antibodies, and adoptive cell therapy. Therefore, blocking the interactions between lymphocytes and LCSCs in combination with immunotherapy may be a promising therapeutic strategy. This review summarizes the interaction mechanisms of lymphocytes and LCSCs and the current exploration of combination therapy in HCC.

Aim: In long-term nucleos(t)ide analog (NA) suppressed patients with chronic hepatitis B (CHB), hepatocellular carcinoma (HCC) can still develop. Few data exist on the incidence and the predictors of HCC development beyond the first five years in long-term treated patients. To assess the prevalence, incidence, and risk factors for HCC development in a real-life cohort of successfully NA-treated CHB patients for more than five years.

Methods: All CHB patients under NAs for ≥ 60 months with stable virologic response were enrolled. HCC surveillance was carried out using liver ultrasound and dosing of serum alpha-fetoprotein every year in patients with CHB and every six months in cirrhotic patients. The baseline PAGE-B score was calculated for each patient.

Results: 343 patients (76% male, 86% HBeAg-negative, 30% cirrhotic) were enrolled. During a median (IQR) follow-up of 144 (105-182) months, 21 patients (6%) developed HCC despite virologic suppression (incidence rate 40 cases/1000 person-years follow-up). In multivariate analysis, higher PAGE B score [adjusted Hazard Ratio, aHR 1.26 (95%CI: 1.13-1.54), P = .022] and cirrhosis [aHR 9.71 (95%CI: 2.02-46.48), P = .005] were predictors of HCC development. PAGE B score showed a significant association with HCC (R² 0.225, P < .001) and good prognostic capacity (AUC 0.863) of HCC.

Conclusions: Our results confirm that in successfully NA-treated CHB patients, sustained viral replication suppression does not abolish the risk of HCC. The PAGE-B score could be a useful tool for identifying high-risk subjects.

Soon after introducing direct-acting antiviral agents (DAAs) for chronic hepatitis C treatment, there began a debate over the possibility of hepatocellular carcinoma (HCC) after viral clearance. Although several reports suggested that the question has been answered negatively, other reports suggested the opposite. The present review presents data in favor and against the null hypothesis and analyzes the scientific background of the possible participation of DAAs in HCC development. The reasons for the discrepancy among studies are presented. These include heterogeneity of patient selection, the nature of the studies, and the tumors themselves are responsible for varying results. Exogenous factors like alcohol consumption or metabolic syndrome confound these findings and suggest the need for statistical adjustments. The need for careful attention to the statistical details is exemplified, and the significant points of almost universal agreements are identified. The conclusion is that the definitive study is impossible for ethical and scientific reasons, and the physician should not ignore even simple personal observations and screening of all patients with extensive fibrosis in HCC, irrespective of sustained virologic response, until a robust, reliable prognostic model can be invented.

Treatment for hepatocellular carcinoma (HCC) has been challenging as most patients present with late, advanced disease, where curative options are limited. For years, locoregional therapy (LRT) has been the first-line therapy for intermediate-stage HCC and sorafenib for advanced HCC. However, these treatments are often palliative since they are plagued by tumor recurrence or progression. Therefore, there is growing interest in combined therapy to utilize their respective strengths to produce synergistic effects. This review outlines past and current research on the efficacy and safety of combined LRT and systemic therapy.

Aim: To describe demographic, clinical, and outcome differences in Pacific Island-born (PI-born) compared to US-born hepatocellular carcinoma (HCC) patients of Pacific Island ancestry within a clinical cohort in Hawaii.

Methods: A prospectively collected database of 1608 patients diagnosed with HCC over a 30-year period (1993-2022) identified 252 patients of Pacific Islander ethnicity. Data collected: demographics, medical history, laboratory data, tumor characteristics, treatment, and survival. Patients were divided into two groups: PI-born and US-born. Categorical variables were analyzed using ANOVA and chi-square analysis. Odds ratios with 95% confidence intervals were calculated using univariate and multivariate logistic regression. Overall survival was evaluated using Kaplan-Meier analysis.

Results: PI-born patients were younger (57.3 vs. 61.8 years, P = 0.002) and more likely to have hepatitis B (OR 14.10, 7.50-26.50) and underlying cirrhosis (OR 2.28, 1.17-4.45). In comparison, US-born patients had a significantly higher likelihood of Hepatitis C, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, history of non-HCC cancer, and positive smoking history compared to PI-born patients. PI-born patients were more likely to forego treatment (OR 3.22, 1.77-5.87) and be lost to follow-up (OR 9.21, 1.97-43.03). Both groups were equally likely to have the opportunity for curative surgical treatment (liver resection or transplant). US-born status was associated with higher mortality risk, while transplantation was associated with lower mortality risk. The PI-born cohort demonstrated higher overall survival at 3 and 5 years compared to US-born.

Conclusion: HBV remains the primary risk factor for HCC in PI-born patients, whereas HCC in US-born patients is more associated with the adoption of a Westernized lifestyle.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and is projected to become a major etiology of cirrhosis and hepatocellular carcinoma (HCC). HCC occurs more commonly in NAFLD patients who develop cirrhosis, though HCC is known to occur in the setting of noncirrhotic NAFLD as well. This is of particular importance given that the American College of Radiology (ACR) CT/MRI Liver Reporting and Data System (LI-RADS) algorithm may only be applied to a certain population of patients, and this population does not include those with noncirrhotic NAFLD. Conventional ultrasound (US) has long been in use for HCC surveillance, but contrast-enhanced US (CEUS) is a relatively newer modality, growing in use for assessment of liver lesions, and its use in HCC diagnosis has been formalized with CEUS LI-RADS. The use of US and CEUS in the assessment of liver lesions in NAFLD patients involves the consideration of certain particular nuances, and familiarity with these considerations will continue increasing in importance as the disease becomes more common.

Cholangiocarcinoma (CCA) is an extremely aggressive neoplasia, mostly because of diagnostic delay and lack of effective therapies. CCA is typically surrounded by a peculiar microenvironment that includes abundant desmoplastic stroma and various cell types, which support and enhance CCA development. Among the tumor microenvironment (TME) cells, there are tumor infiltrating lymphocytes (TILs), such as CD8⁺ and CD4⁺ cells, Tregs, natural killers (NKs) and B lymphocytes. TILs contribute to an immunosuppressive microenvironment that leads to tumor immune escape. Dendritic cells (DCs) may lead to immunotolerance by maturation or antigen-presentation deficiency. Hepatic stellate cells (HSCs) are one of the major precursors of cancer-associated fibroblast (CAFs), which are distinguished in various subpopulations, each with different functions and interactions with other TME cells. CAFs can promote lymphangiogenesis, early lymph-node metastasis and proinflammatory environment, but they can also provide a physical and chemical barrier to protect CCA. Tumor-associated macrophages (TAMs) could be differentiated between two phenotypes, pro- and anti-inflammatory, and they may sustain invasiveness and immunosuppression. Myeloid-derived suppressor cells (MDSCs) impair cytotoxic T lymphocytes (CTLs) function, stimulating tumor proliferation and angiogenesis. Tumor-associated neutrophils (TANs) function is influenced by the TME, leading to tumor-suppressing or tumor-promoting functions. This paper aims to provide an overview of the CCA microenvironment cells, their role in tumor progression and possible correlated diagnostic, therapeutic and prognostic implications.

Perihilar cholangiocarcinoma (pCCA) is a challenging disease with limited options. Surgical resection and adjuvant therapy remain the only established treatment for those with resectable disease. Since the publication of the Mayo protocol in 2000, neoadjuvant chemoradiation and liver transplantation have become the standard of care in selected patients with unresectable de novo pCCA or resectable pCCA arising under primary sclerosing cholangitis. However, its application is diverse worldwide, and the need for donor organs is one of the main limitations. Also, differences in the neoadjuvant regimen used were observed. In this review, we discuss the latest results of this approach, the recommended tools for diagnostic work-up, and advances in systemic therapy to improve patient selection and long-term survival.

The proportion of hepatocellular carcinoma (HCC) cases due to NAFLD is expected to increase, paralleling the rise in NAFLD due to the obesity epidemic. Early detection is critical, as it potentially enables curative treatment. Current guidelines recommend ultrasound imaging with or without serum AFP measurement in patients with cirrhosis. Unfortunately, several challenges and barriers impede the effective surveillance of HCC in patients with NAFLD. In this review, we focus on four main challenges and barriers: the scale of the NAFLD epidemic, the lack of accurate risk stratification tools, the limitations of available surveillance tools themselves, and the existing disparities in access to care for chronic liver disease. We describe potential solutions, including public health approaches to obesity, improving clinical risk scores using genomic and metabolomic data, improved imaging techniques and blood-based biomarkers, and focusing on underserved groups with liver disease.

International guidelines recommend six monthly ultrasounds as the primary surveillance tool for patients at risk of hepatocellular carcinoma (HCC). The dominant driver of liver disease in HCC surveillance populations is shifting, particularly in Europe and the United States, from chronic viral hepatitis (B or C), towards non-alcoholic fatty liver disease (NAFLD). Today, the population requiring HCC surveillance is also characterised by a high prevalence of overweight/obesity. These patient characteristics significantly impair ultrasound quality which can impede the detection of early HCC lesions. This diagnostic limitation has significant implications considering that eligibility for curative treatment depends upon the stage at which the cancer is detected. In this narrative review, we provide a comprehensive overview of the published evidence and national/international guidelines regarding ultrasound surveillance for HCC in people with NAFLD. We examine ultrasound sensitivity in this cohort for the detection of all stage and early HCC, the impact of steatosis and abdominal obesity on ultrasound performance, evidence for the addition of serum alpha-fetoprotein measurement, optimal timing of surveillance, emerging modalities for risk stratification and screening, and outline the challenges of case finding and surveillance eligibility criteria in this patient cohort. Finally, amalgamating all available evidence, we propose a pragmatic surveillance pathway for patients with NAFLD.

The aim of this review is to describe the relevance of minimally invasive liver resection (MILR) for the treatment of most common primary liver tumors. The uptake has been slow but steady, and thus MILR has become a well-established field of hepatobiliary surgery and is considered a landmark change of the past 30 years. There is evidence that the advantage of MILR regarding specific complications of liver surgery for HCC (reduced incidence of postoperative hepatic decompensation and ascites) can be a tool to potentially expand the indications to surgical treatment. Evidence for intrahepatic cholangiocarcinoma is early and exploratory; however, it is beginning to be documented that the fundamental principles of surgical oncology for this tumor can be respected while offering patients the advantages of minimal invasiveness.

The role of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) management has changed over the last twenty years. There has been a trend towards an overall decline in TACE procedures, but with a more aggressive approach, repeating multiple TACE sessions in case of tumor response. The survival of treated patients was prolonged because of better patient selection and advancements in TACE techniques aimed at preserving liver function. At present, TACE is approved by the International Guidelines also outside of the BCLC intermediate stage after evaluation of a multidisciplinary tumor board (MDTB), permitting a customized treatment for every patient. An alternative therapeutic strategy is represented by hepatic chemoembolization with Degradable Starch Microspheres (DSM-TACE), which is based on the chemotherapeutic effect rather than on the ischemic damage to the liver tumor, requiring multiple cycles of treatment. The higher safety profile of DSM-TACE has broadened the indications to patients waiting for liver transplantation (with bridging or downstaging intention), at high risk of liver failure and ineligible for systemic therapies. This review summarises the scientific publications supporting the use of DSM-TACE and illustrates its indications depending on the disease stage from the Interventional Radiologist’s perspective.

Intrahepatic cholangiocarcinoma (iCCA) is a rare neoplasm of the bile ducts with a low survival rate, whose incidence is continuously increasing and is associated with a rich and varied tumor microenvironment (TME). Although the main mutations characterizing iCCA are known, there are several unresolved issues regarding the processes leading to the accumulation of mutations in the normal cholangiocyte. The inflammatory mediators and the molecular pathways involved in cholangiocarcinogenesis, which regulate the transition from normal to dysplastic cells, resulting in neoplastic cholangiocytes, are poorly understood. Moreover, once the tumor is established, it is unclear which effects of the interaction between the tumor and TME constituent cells, in particular cancer-associated fibroblasts (CAFs), are responsible for stimulating the malignant behavior of iCCA. In this review, we described the main mutations affecting the bile ducts leading to iCCA development as well as the putative inflammatory mediators and morphogenetic pathways involved in the establishment of the malignant transition of the bile ducts. We also described the main signaling pathways involved in TME-tumor cell interactions, with particular emphasis on the effect of CAFs in cancer. Finally, we wanted to analyze possible new therapeutic approaches aimed at modifying the composition of TME and the possible role of immunotherapy in improving the treatment of this cancer.

Combined Hepatocellular-Cholangiocarcinoma is a heterogenous primary malignant epithelial tumor of the liver with variable morphological and immunophenotypical features. Although the biology of this tumor has been described in the literature, changes in classification and its heterogeneity imply difficulties in collecting reliable homogenous groups to compare. The article aims to review available data on morphology and immunohistochemistry for practicing pathologists integrated with original data from our referral Center.

Intrahepatic cholangiocarcinoma (ICCA) is a rare tumor with a poor prognosis that arises from the intrahepatic biliary tract. Patients who present with locally advanced or metastatic ICCA are generally treated with first-line gemcitabine/cisplatin and/or liver-directed therapy with the hope of downstaging/downsizing the disease. Patients who present with resectable ICCA may be treated with upfront surgery and postoperative adjuvant capecitabine. Staging laparoscopy should be considered to evaluate for occult metastatic disease and laparoscopic ultrasound can be used to better evaluate the liver parenchyma. Resection with the goal of achieving an R0 margin, along with lymphadenectomy to adequately stage patients, should be the standard operative approach. Unfortunately, the surgical technique cannot overcome poor tumor biology, and ICCA has a high incidence of recurrence, with many patients developing metastatic disease. Targeted therapy with IDH and FGFR inhibitors has had promising results in early clinical trials. Future endeavors should strive to identify more effective systemic and targeted therapies, which will hopefully improve survival for patients with ICCA.

There are significant ethnic disparities in incidence, tumor stage, curative therapy receipt, and survival among patients with hepatocellular carcinoma (HCC) in the US. While previous models had predicted an increasing trend in the incidence rate of HCC until 2030 in the US, recent studies have shown that HCC incidence plateaued in 2013 and then started to decline in 2015. The decreasing trend has been observed in all ethnicities except for American Indians/Alaska Natives, whose incidence rates of HCC continue to rise. Current evidence shows that African-Americans and Hispanics are two groups that are more likely to be diagnosed with late-stage HCC, and this finding has been consistent in different socioeconomic statuses of the patients. These two ethnic minority groups are also among those who are less likely to have curative therapy for early-stage HCC. Finally, advances in early diagnosis and treatment approaches have led to an improvement in HCC survival for all ethnicities; however, African-Americans continue to have the worst survival. More studies to find the causes of these disparities and interventions to eliminate them are urgently needed.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy that originates from the biliary tract located within the liver parenchyma. While the incidence rate of iCCA is increasing worldwide, the existing therapeutic options still remain limited. Thus, the spread of iCCA is the foremost cause of treatment failure representing a major clinical challenge. The aggressive nature and refractoriness of the iCCA are strictly related to the desmoplastic tumor microenvironment, in which cancer cells are surrounded by inflammatory cells, cancer-associated fibroblasts, and the aberrant deposition of members of the collagen family. In recent years, accumulating evidence revealed that remodeling of collagens is pivotal in driving the dissemination of desmoplastic cancers. In this review, we describe the expression profile of collagens and their unique architecture in iCCA and how this can dictate neoplastic cell behavior. The emerging view argues for specific strategies aimed at targeting the collagen architecture that may be useful to hamper iCCA metastasis.

Liver transplantation is one of the more definitive treatments for hepatocellular carcinoma (HCC). In the United States, liver transplantation has historically been focused on deceased donor organs, and tumor burden is used for risk-stratifying patients on the transplant waitlist. Living donor liver transplantation (LDLT) is gaining popularity in the United States and has long been practiced in Asian countries. To improve outcomes of overall survival and disease-free survival post-living donor liver transplantation, surrogates of tumor biology are now being regarded to be as important as tumor burden. This article reviews the different surrogates of tumor biology and discusses their role in the application of LDLT for advanced HCC.

There are multiple liver-directed treatment options for hepatocellular carcinoma (HCC), which provide curative intent, help patients achieve remission, and/or provide a bridge to transplant by controlling local tumor progression and downstaging patients. After locoregional therapy (LRT), management of these patients, including liver transplant candidacy, is guided by treatment response assessment. The Liver Imaging Reporting and Data Systems (LI-RADS) treatment response algorithm (TRA) was created to provide a standardized assessment of HCC following LRT. Originally created primarily on expert opinion, subsequent literature has continued to evaluate the validity of this algorithm. In this manuscript, we review emerging literature supporting the use of LI-RADS in the assessment of HCC treatment response after LRT and highlight future updates.

Chronic liver disease is an important risk factor for the development of hepatocellular carcinoma (HCC), with 80%-90% developing in the background of cirrhosis, primarily due to alcohol abuse and chronic viral infection with hepatitis B and C. Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) related HCC is rising due to the global epidemic of obesity and diabetes. NAFLD also potentiates other risk factors of HCC, such as chronic hepatitis C and alcoholic liver injury. Furthermore, HCC may complicate non-cirrhotic NAFLD, greatly expanding the population potentially at risk. Screening and surveillance for HCC with ultrasonography (US) in this patient population pose challenges related to body habitus, liver morphology, and co-morbidities. Magnetic resonance imaging (MRI) applying various image sequence protocols and contrast agents could aid in early detection and improved prognosis of HCC. It is of utmost importance to define the most cost-effective dynamic imaging protocol for use in patients where high-quality ultrasonography images cannot be obtained and for patients undergoing surveillance for lesions identified with US. Furthermore, standardization of MRI protocols will help to define potential unique HCC features in this population. A scoring system including patient-derived factors may help to identify high-risk patients. Standardized protocols as part of prospective cohort studies and randomized clinical trials will help to stratify high-risk patients and to aid the development of professional guidelines for screening and surveillance of HCC in patients with NAFLD and NASH using dynamic imagining techniques.

Intrahepatic cholangiocarcinoma (iCCA) is a rare liver cancer generally associated with poor patient outcomes. Curative intent liver resection has been established as a standard treatment of care of resectable disease. However, the role of lymphadenectomy, including the extent of resection and therapeutic value, continues to be an area of controversy. The objective of this review was to highlight the role of lymph node dissection (LND) relative to therapeutic value and prognosis in the surgical management of iCCA. A comprehensive review was performed using MEDLINE/PubMed. Search terms included “intrahepatic cholangiocarcinoma”, “bile duct cancer”, "lymphadenectomy”, “lymph node metastasis”, and "lymph node staging”. Treatment for iCCA should include an R0 resection with regional lymphadenectomy. The prognostic and therapeutic value of regional lymphadenectomy has been an increased area of research and debate. An increased number of lymph node metastases has correlated with inferior overall survival versus lymph node-negative disease. In addition to surgical resection, regional lymphadenectomy with the removal of at least six lymph nodes in the appropriate nodal basins based on primary tumor location should be standard. The identification of lymph node metastasis provides additional important information to guide providers in determining adjuvant therapy and surveillance strategies.

Cholangiocarcinoma (CCA) is a primary liver cancer whose diagnosis and treatment remain challenging. Although recent developments derived from molecular characterization of CCAs have led to the availability of new pharmacological agents, a better understanding of the genetic and molecular alterations in CCA is still required for the development of more effective or broader targeting treatments. One emerging signaling pathway of interest in the pathogenesis of CCA is ER to mitochondrial Ca²⁺ signaling. This pathway is of particular importance because it regulates both cell death through apoptosis and necrosis, and metabolic reprograming of cancer cells through regulation of energy metabolism in mitochondria. Here we discuss the latest findings regarding the dysregulation of mitochondrial Ca²⁺ signals and its key regulatory molecules with a special focus on the intracellular Ca²⁺ channels of the inositol 1,4,5-trisphosphate receptor (ITPR) family. We also discuss the role of ER-mitochondrial contact sites in determining mitochondrial health and how these points of contact between organelles might represent a druggable target in CCA.

The global morbimortality of biliary tract cancer (BTC) is steadily increasing and accounts for ~10% of all primary liver cancer. Distinct anatomical locations of BTC have singularities in their etiopathogenesis, which are translated into differences in their molecular fingerprints and the associated therapeutic approaches. Extrahepatic cholangiocarcinoma (eCCA), arising in the large and distal bile ducts, presents recurrent activating mutations of KRAS and loss-of-function alterations in TP53, SMAD4, and CDKN2A/B. Despite being highly prevalent, no targeted therapies are yet available for these oncogenic drivers. ERBB2 mutations and amplifications, on the other hand, are the most recurrent actionable alterations for eCCA, with several clinical trials aiming to provide benefits in biomarker-enriched populations. In addition, integrative multi-omics analysis of eCCA has allowed the identification of novel molecular classes of this disease that could be therapeutically exploited. Beyond that, the highly immunosuppressive tumor microenvironment of eCCA has prevented until now the success of immune checkpoint inhibitors, recently approved in combination with cytotoxic chemotherapy. Further characterization of eCCA at the molecular level would potentially foster treating patients based on a precision oncology approach in order to increase the clinical outcomes for this challenging disease.

Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive form of primary liver cancer that presents significant diagnostic and treatment challenges. In this review, we discuss the role of diagnostic radiology in the management of ICC, and future directions for research and clinical practice in the management of ICC.

Liver transplantation has emerged as a potential therapeutic option for select patients with intrahepatic cholangiocarcinoma (iCCA) who are not amenable to curative resection. Recent studies have challenged the traditional notion that liver transplantation is contraindicated for iCCA, leading to a paradigm shift in its management. This review provides a comprehensive synthesis of the evidence regarding the role of liver transplantation in the treatment of very early or advanced iCCA and discusses the key challenges and future directions in this rapidly evolving field. For patients with cirrhosis and very early iCCA, liver transplantation has demonstrated excellent long-term survival rates, rivaling those of patients with hepatocellular carcinoma. However, the current transplantation criteria based on tumor size and number may be overly restrictive, excluding potential candidates who could benefit from this treatment. The incorporation of tumor markers into selection criteria may improve prognostic prediction and patient outcomes. In advanced iCCA, liver transplantation remains controversial but holds promise, especially when combined with neoadjuvant and adjuvant therapies. Donor organ scarcity necessitates the consideration of living donor liver transplantation as an alternative, while strategies such as utilizing marginal donors and exploring xenotransplantation offer potential solutions to address the shortage of donor livers. Overall, the evolving understanding of iCCA and the development of novel treatment strategies promise to refine and enhance the role of liver transplantation in the management of this challenging malignancy.

Cholangiocarcinoma (CCA) is an extremely aggressive malignancy characterized by a very limited prognosis and scarce treatment options. The majority of patients are diagnosed at an advanced stage and do not qualify for potentially curative surgical treatments, making CCA an increasingly prevalent global challenge. CCA is characterized by a highly reactive desmoplastic stroma, with complex mechanisms underlying the mutual interactions between tumor cells and stromal compartment. This review focuses on the recent studies examining CCA’s biological features, with particular reference to the tumor reactive stroma (TRS) and its role in CCA progression, including matrix remodeling, angiogenesis and lymphangiogenesis, metastasis, and immune evasion. After giving a panoramic view of the relationship between the tumoral and stromal compartment (cancer-associated fibroblast, CAFs and tumor-associated macrophages, TAMs), this review also discusses the current therapeutic approaches to counteract CAFs and TAMs effects on CCA progression.

Intrahepatic cholangiocarcinoma (ICCA) incidence has been rising in the last few decades. Currently, hepatic resection is the only curative treatment for ICCA, and there is a lack of evidence supporting the use of preoperative treatment. A narrative review was conducted to analyze the available literature published on the role of neoadjuvant chemotherapy (CHT), either alone or combined with intra-arterial therapies (IAT), for downstaging unresectable ICCA to surgical resection. Most of the studies included in this review showed that secondary resection was associated with improvement in overall survival. In particular, studies analyzing CHT alone reported the highest conversion rate ranging from 20% to 57.1%, confirming that systemic treatment may yield the best results, and therefore, it should always be included as part of the neoadjuvant protocol. Among all the IATs, the longest overall survival reported was after CHT plus hepatic artery infusion, 25 months. Downsizing neoadjuvant multimodal approach, including combined systemic therapy with IAT, might improve the long-term outcomes of unresectable patients and expand surgical indications. However, randomized controlled trials are necessary to confirm their effectiveness.

Cholangiocarcinoma (CCA) grows within a highly desmoplastic microenvironment, exhibiting a continuous interconnection with the immune infiltrate, which is characterized by an abundance of immune cells, including natural killer cells, T lymphocytes, and macrophages. The presence of inflammatory cells within the tumor microenvironment plays a crucial role in determining the aggressiveness and growth of CCA. The immune cell population engages in diverse and dynamic interactions with cancer cells. The balance of different subpopulations within CCA can generate varying responses, either inhibiting or promoting tumoral progression. The purpose of this review is to offer a comprehensive overview of the role of various immune infiltrate subpopulations within the tumor microenvironment, with a particular focus on the actions of tumor-associated macrophages (TAMs) and their critical regulation in the development and progression of CCA. TAMs play vital roles in maintaining homeostasis, facilitating tissue repair, and contributing to immune responses due to their significant functional diversity. Macrophages are present in numerous types of cancer, and their emerging role has also been observed in CCA. Recognizing and attaining a deeper comprehension of the intricate interplay between infiltrating immune cells and CCA cells is essential to identify new opportunities to advance treatment strategies.

Intrahepatic cholangiocarcinoma (iCCA) is a rare tumor that arises from second order or smaller bile ducts. Its incidence has been growing in the last couple of decades, in parallel with its mortality rates, both in America and Europe. The currently accepted gold treatment for iCCA is liver resection (LR). However, results are still poor, with 5-year survival rates ranging between 25% and 40%. In addition, more than half of the patients undergoing LR will relapse, particularly those who present with multifocal iCCA. Given the aggressiveness of this tumor, and the modest results seen with adjuvant and neoadjuvant therapies, the sights have been set on liver transplantation (LT) for this disease. Retrospective studies have shown encouraging results in select patients, especially those with very early-staged iCCA (< 2 cm) who underwent LT. The aim of this review is to analyze the current information regarding LT for iCCA, as well as future perspectives.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive and heterogeneous biliary cancer with a poor prognosis and limited treatment options. The molecular pathogenesis of iCCA involves a highly complex process entailing multiple genetic alterations and dysregulation of signaling pathways. Recent advancements in our understanding of the genetic landscape of iCCA have opened new opportunities for therapeutic interventions. Technologies such as next-generation sequencing (NGS) have contributed to elucidating the genetic heterogeneity of iCCA, leading to the identification of numerous potentially actionable genetic alterations. Despite these advances, the prognosis of iCCA patients remains dismal. In this review, we provide an extensive summary of the current knowledge on genetic alterations in iCCA, their biological impact on patients, potential therapeutic targets, approved targeted therapies, and ongoing clinical trials with targeted agents. Furthermore, we discuss the main technologies available for studying genetic alterations and their advantages and limitations. Finally, we highlight future directions in studying genetic alterations and the development of new targeted therapies and personalized medicine approaches.

The heterogeneity of tumors results in significantly distinct biological characteristics of intrahepatic cholangiocarcinoma (ICC) caused by different etiologies. Among them, ICC caused by intrahepatic lithiasis (IHL-ICC) presents challenges in early detection, tumor staging, and surgical treatment, and has the poorest prognosis among all etiologies of ICC patients. Thus, it is essential to focus on early assessment of the possibility of developing ICC, prompt intervention of intrahepatic lithiasis, anatomical resection of hepatic parenchyma corresponding to the branch of the intrahepatic bile duct undergoing cancerous transformation, and enhanced postoperative follow-up of hepatolithiasis and ICC for IHL-ICC patients. These interventions are crucial to improve the clinical outcomes and overall survival of IHL-ICC patients.

The treatment of intrahepatic cholangiocarcinoma (iCCA) has traditionally been limited to surgical resection or systemic therapy. The role of liver transplantation in the management of iCCA is a topic currently being explored. This paper serves as a review to highlight past, present, and future work being done in regard to liver transplantation for iCCA. Strict protocols with specific selection criteria have shown promising results. Neoadjuvant therapy, locoregional therapy, and immunotherapy are some of the tools that may aid in bridging selected patients with iCCA to liver transplantation. There are currently three ongoing trials designed to further evaluate the efficacy of liver transplantation for iCCA. As criteria continue to be refined and evidence accumulates, liver transplantation may become a suitable option as a curative treatment strategy for highly selected patients with unresectable intraoperative cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive malignancy that arises from the biliary tract. Currently, the first-line therapy for advanced CCA is gemcitabine and cisplatin. However, 5-year survival remains low. It has become abundantly clear that a “one size fits all” approach no longer applies to the treatment of individual cancers, given the large amount of tumor heterogeneity. As such, research in recent years has focused on developing effective targeted therapies through genetic profiling of CCA tumors. IDH1 and IDH2 mutations are commonly found in intrahepatic CCA (ICCA). IDH mutations prevent hepatic progenitor cell differentiation and result in the persistence of progenitor-like and stem cells. These are more prone to alterations that promote tumor initiation. As such, IDH has been identified as a promising target for ICCA treatment. We herein review the role of IDH mutations in ICCA development, recent data for IDH inhibitors in ICCA treatment, and challenges within the field of targeted therapy for ICCA.

Aim: Liver transplantation (LT) offers a potential curative treatment for non-metastatic intrahepatic cholangiocarcinoma (iCCA) in patients with chronic liver disease who are not amenable to liver resection (LR). Recent evidence suggests that cirrhotic patients with “very early” iCCA (single tumour, ≤ 2 cm) might benefit the most from LT, with a 5-year survival as high as 73%. In view of these developments, NHS Blood and Transplant’s Liver Advisory Group (LAG) established a Fixed Term Working Group (FTWG) to determine whether iCCA in patients with background cirrhosis should be considered for LT in the United Kingdom.

Methods: The FTWG included cholangiocarcinoma/LT patient representatives, experts in cholangiocarcinoma surgery/oncology, LT surgery, hepatology, hepatobiliary radiology, hepatobiliary pathology, nuclear medicine, and representation from various national hepatobiliary/oncology and transplant professional bodies. The objective was to make recommendations on appropriate indications, patient selection criteria, referral criteria, radiological assessment, transplant listing pathways, data management, and overall quality assurance.

Results: The FTWG recommended LT for very early iCCA in cirrhotics, who are otherwise not suitable for LR. In this paper, we summarise the selection criteria, patient pathways, referral framework, pre-transplant assessment criteria, outcome measures, and dissemination strategy for implementing this new indication for LT in the UK.

Conclusion: The introduction and evaluation of this pilot programme is an important breakthrough for iCCA patients in the UK, marking a significant stride in the field of transplant oncology. The results of this service evaluation will describe the role of LT in iCCA and guide future programmes to optimise patient selection, management, and outcomes.

Liver cancer is the sixth commonest cancer and the third leading cause of cancer mortality worldwide. Accumulating evidence suggests a pivotal role of the gut microbiome in the progression of chronic liver disease and the subsequent development of liver cancer. Additionally, gut microbiome has been shown to contribute to the hosts’ antitumor responses following immunotherapy and chemotherapy for liver cancers, highlighting the therapeutic potential of gut microbiome modulation in enhancing treatment efficacy and reducing drug resistance. Fecal microbiota transplantation (FMT), a novel therapeutic modality to deliver a healthy donor's stool by endoscopy or capsule, has demonstrated potential in managing liver diseases and cancers by restoring and modulating the recipient’s gut microbiome composition. However, existing data on the clinical application of FMT in liver cancers are still limited. This review summarizes the underlying roles and mechanisms of gut microbiome in liver cancer and discusses the therapeutic potential of FMT in liver cancer treatment and the management of its related complications (e.g., hepatic encephalopathy).

Radiotherapy (RT) is an integral component of the multidisciplinary care for intrahepatic cholangiocarcinoma (iCCA). Over the past decades, RT techniques have been developed with the aim of enhancing tumor control and minimizing toxicity. The most recent technological advancements include proton beam therapy (PBT) and magnetic resonance-guided radiotherapy (MRgRT). PBT is notable for its unique physical characteristics that allow for greater sparing of surrounding normal organs, especially the liver, from low to moderate doses of radiation. MRgRT provides advantages in other aspects, including superior tumor visualization before treatment, on-board treatment plan adaptation, and tumor tracking during treatment. These features allow for precise dose delivery and safe dose escalation, especially for patients with tumors close to luminal GI structures. In this review article, the rationale, clinical outcomes, clinical applications, challenges, and future directions of PBT and MRgRT are discussed. Additionally, the potential combination of novel therapeutics with RT in iCCA is explored.

The tumor microenvironment (TME) constitutes a complex structure comprising different cell types and soluble factors that surround the tumor and promote its progression. Primarily for its pivotal role in malignant growth, TME has become a potential therapeutic objective for developing new targeted therapy and a marker for assessing therapeutic response. In intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver malignancy, TME has also gained a central role in understanding the mechanisms underlying tumor progression. In this review, we focused on the role of angiogenic factors and their pathway in iCCA and analyzed possible therapeutic and prognostic implications.

Considering the steadily growing incidence of cholangiocarcinoma (CCA) worldwide, there is a constant need to re-evaluate and re-think its pathophysiology, diagnostic modalities, and mostly important, its treatment. No matter the histopathological appearance, endoscopic procedures - mainly Endoscopic Retrograde Cholangiopancreatography (ERCP) with stenting - are often used in the treatment of CCA complications, such as biliary obstruction when biliary drainage is indicated. Indications for preoperative biliary drainage in surgical cases are adjusted to each patient’s status. On the contrary, palliative drainage is the first option for relieving symptoms and improving the quality of life in the context of locally advanced and unresectable CCA. Further, concern about stenting techniques depends on the stricture location: Bismuth-Corlette types I and II are usually endoscopically drained with one stent placed in biliary tract, while for types III and IV, even bilateral stenting may prove inadequate. Stents used in ERCP are either plastic or self-expandable metallic stents (SEMS). Though plastic stents show some advantages over SEMS in terms of removability and possibility to adapt to a biliary tree which allows potential reinterventions, SEMS are better in terms of patency, lower complications number, and success of drainage. Besides ERCP, echo-endoscopic drainage is also an option, especially when ERCP approach has not yielded a successful drainage. The aim of this study was to show the potential of ERCP stenting in CCA treatment, its possible pitfalls, and the need to consider multiple levels of ERCP-related care.

Trans-arterial therapies performed by interventional radiology, including chemoembolization and radioembolization, have been increasingly utilized for the treatment of unresectable intrahepatic cholangiocarcinoma. There is increasing evidence demonstrating the safety and efficacy of these interventions in patients with advanced disease. This review provides an overview of trans-arterial chemoembolization and radioembolization for unresectable intrahepatic cholangiocarcinoma, summarizes current evidence, and explores future directions for locoregional therapies.

Intrahepatic cholangiocarcinoma (iCCA) is a rare cancer with generally poor prognosis. In this narrative review, we examine the role of thermal ablation and summarize the current literature. Radiofrequency ablation (RFA) and microwave ablation (MWA) are both safe and well-tolerated as a minimally invasive local curative treatment option for patients suffering from primary and secondary liver tumors. Both methods can be used in patients with medical morbidities that would preclude surgery, as well as individuals with anatomical or functional constraints that impede liver resection. In unresectable iCCA, the median OS after conventional percutaneous US- or CT-guided RFA and MWA is between 20 and 39 months and 10 and 28 months, respectively. In recurrent iCCA, percutaneous RFA and MWA achieved a median OS of 21-27 months and 21-31 months, respectively. These data are comparable to long-term outcomes after surgical resection (SR), with the number of nodules and tumor size affecting prognosis. Stereotactic radiofrequency ablation (SRFA) allows for effective treatment of large and multiple iCCA nodules within one session and achieves short- and long-term results in inoperable patients compared with resection. With the addition of SRFA as an alternative treatment option, the proportion of patients who can be treated with curative treatment has significantly increased. In the absence of prospective trials comparing thermal ablation and surgical resection, we recommend a patient-specific decision-making process. Future research to identify technical and clinical prognostic criteria, as well as molecular markers of tumor biology, may help select patients for ablation and subsequent outcomes.

Aims: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. While patients who are known to be at high risk for HCC should be under surveillance, only 20% of eligible patients in the United States are surveilled. The aim of this study was to identify providers’ perspectives about patient-, provider- and system-level barriers to surveillance for HCC among high-risk patients and to examine provider knowledge and attitudes related to HCC surveillance. We also explored interventions providers suggested as ways to improve HCC surveillance.

Methods: Purposive sampling was used to recruit physicians and nurse practitioners in hepatology, gastroenterology, and primary care (internal and family medicine) from one academic medical center to participate in semi-structured interviews. Interviews were transcribed verbatim, and analyzed deductively and inductively to reveal emergent themes.

Results: 22 informants were interviewed. During these interviews, several important themes emerged, including: (1) Provider comfort with managing chronic liver disease and the relationships between hepatology, gastroenterology, infectious disease, and primary care providers; (2) Provider knowledge of guidelines for HCC surveillance in high-risk patients and their knowledge about the impact that HCC surveillance can have; (3) How providers discuss HCC surveillance with their high-risk patients; (4) Provider-Level barriers to surveillance; (5) System-level barriers to surveillance; (6) COVID-19; (7) Patient-level barriers to surveillance, and (8) Suggested interventions to improve HCC surveillance rates.

Conclusions: In designing interventions to improve HCC surveillance rates of high-risk patients in the United States, there are important targets at the patient, provider and system levels.

Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignant tumors globally. Despite considerable advancements in HCC therapies, therapeutic resistance remains a significant challenge that compromises patient prognosis. Increasing evidence indicates that exosomes, which are secreted by cells in the tumor microenvironment (TME), are pivotal players in the development of therapeutic resistance in HCC. These nano-sized vesicles mediate intercellular communication in TME through the transfer of bioactive molecules such as nucleic acids, lipids, and proteins. A comprehensive understanding of the role of exosomes in therapeutic resistance could provide promising strategies for both the diagnosis and treatment of HCC. This review mainly summarizes the involvement of exosomal cargos and elucidates their underlying mechanisms in resistance to therapeutic treatments for HCC, and further discusses the potential clinical applications of exosomes as diagnostic biomarkers and therapeutic targets to overcome drug resistance in HCC.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, deriving from the neoplastic transformation of hepatocytes, most often forced to long-lasting regeneration by the cirrhotic background. HCC is an extremely aggressive tumor with still limited effective treatments, and is characterized by the presence of a very complex and multifaceted tumor microenvironment (TME). Among the variety of cell types populating the TME of HCC, cancer-associated fibroblasts (CAFs) are the most prevalent. CAFs are a specific population of fibroblasts in a persistent state of activation, with a high level of heterogeneity, partly dependent on a wide range of cell origin, which are endowed with a repertoire of functions, profoundly modulating the biology of the tumor. Given the close relationship of HCC with cirrhosis, CAFs are paradigmatic of the role played by activated fibroblasts in promoting the evolution of a chronic, non-resolving, fibro-inflammatory condition towards a neoplastic disease and its aggressive phenotype. In this review, we will discuss the most recent findings regarding the interplay of CAFs with the tumoral epithelial compartment, with the multiple cell elements of the TME (macrophages, neutrophils, myeloid-derived suppressor cells, vascular cells), and with the extracellular matrix. Finally, we will address the translational value of CAF manipulation in HCC to unveil possible ameliorations for the treatment of a still worrisome disease.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver cancer with limited treatment options and poor prognosis. Although gemcitabine combined with cisplatin (GEMCIS) or newly GEMCIS plus durvalumab is the first-line systemic therapy for iCCA, several promising treatment targets have been identified in the past decade in both first- and subsequent-line settings, including neurotrophic tropomyosin-receptor tyrosine kinase (NTRK) fusions, RET fusions, high microsatellite instability (MSI-H), high tumor mutation burden (TMB-H), as well as fibroblast growth factor receptor 2 (FGFR2) fusions, BRAF V600E mutation, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and human epidermal growth factor receptor 2 [HER2 (ERBB2)] amplifications. Corresponding small molecule inhibitors and monoclonal antibodies have demonstrated improved efficacy and survival benefits in phase 2 or phase 3 studies, gained regulatory approvals or recommendations in guidelines, and reshaped the therapeutic management for advanced cholangiocarcinoma. Numerous novel targeted drugs and combination therapies have been developed and are under evaluation. Despite the progress made in targeted therapy, it still faces challenges such as acquired drug resistance, precise patient selection, and serious adverse events. Therefore, large-scale randomized phase 3 trials of novel targeted agents and innovative regimens are warranted to benefit this population. Herein, we present a comprehensive review of the literature of clinical significance on targeted therapy for iCCA in recent years, focusing on the advances in mutation-based targeted therapy.

Liver transplantation is considered the gold standard for curative treatment of hepatocellular carcinoma (HCC) in patients with cirrhosis, but limited organ availability and high costs necessitate alternative options. Hepatic resection (HR) is preferred for select patients, providing tumor removal and prognostic information. However, HR has been associated with life-threatening complications, especially in the presence of clinically significant portal hypertension (CSPH). Current guidelines recommend HR only for patients with well-preserved liver function, normal bilirubin levels, good performance status, and no CSPH. However, advancements in surgical techniques and portal hypertension management are challenging these guidelines, potentially allowing the consideration of hepatic resection for HCC in cirrhotic patients with CSPH. Indeed, minimally invasive approaches improve safety and outcomes for selected CSPH patients and accurate assessment of CSPH allows risk stratification according to liver function, tumor location, and extent of resection. Thus, despite the negative impact of CSPH on HR outcomes, careful patient selection and minimally invasive techniques expand the potential for HR in CSPH patients. This comprehensive review examines the evidence on HR in HCC treatment for cirrhotic patients with CSPH, highlighting challenges in surgical decision-making, the importance of direct measurement of hepatic venous pressure gradient, and exploring the benefits and risks associated with HR. Moreover, it underscores the need for refined prediction models and algorithms to optimize patient selection and enhance surgical outcomes.

My invited commentary discusses a recent paper published by Ebrahimi et al.^[28]. To this end, the definitions of nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), and the most recently proposed metabolic dysfunction-associated steatotic liver disease (MASLD) are reviewed. For brevity, the overarching definition of metabolic fatty liver syndromes (MFLS) is utilized to allude to NAFLD/MAFLD/MASLD collectively, although each nomenclature identifies different diagnostic criteria and distinct patient populations. Ebrahimi and colleagues conducted an analysis using data from the National Swedish Multigeneration archive, involving 38,018 MASLD first-degree relatives (FDRs) and 9,381 MASLD spouses, alongside 197,303 comparator FDRs and 47,572 comparator spouses. These authors followed these groups for a median of 17.6 years and reported a definite familial aggregation of adverse liver-related events among families of MASLD individuals. These events comprise increased relative risks of hepatocellular carcinoma (HCC), major chronic liver disease, and mortality owing to hepatic causes. I comment on this study with reference to the ongoing changes in terminology describing MFLS and to sexual dimorphism exhibited by MFLS. It is concluded that the study by Ebrahimi adds another piece to the puzzle of knowledge requested to implement those precision medicine approaches that are eagerly awaited in the field of MFLS.

Over the last two decades, substantial progress has been made in the scope of molecular targeted therapy, leading to transformative advancements in the treatment of various malignancies, including biliary tract cancer (BTC). BTC represents a heterogeneous group of aggressive tumors with historically poor prognoses. However, recent discoveries of novel molecular alterations in BTC have provided new avenues for targeted therapeutic interventions, exemplified by the approval of pemigatinib, specifically designed for FGFR2 gene fusions or rearrangements in advanced BTC. Furthermore, subsequent regulatory approvals and ongoing clinical trials focusing on specific gene mutations have considerably expanded the array of treatment options available, augmenting the potential for personalized treatment strategies. In light of these developments, this review aims to furnish a comprehensive and up-to-date account of the molecular characteristics and potential targeted therapies in BTC. By presenting insights into novel therapeutic approaches and outlining prospective directions for translational and clinical investigations, this review seeks to contribute to the ongoing progress and optimization of therapeutic approaches in managing BTC.