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The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma.

ABSTRACT: Biliary tract cancer, and intrahepatic cholangiocarcinoma (iCC) in particular, represents a rather uncommon, highly aggressive malignancy with unfavorable prognosis. Therapeutic options remain scarce, with platinum-based chemotherapy is being considered as the gold standard for the management of advanced disease. Comprehensive molecular profiling of tumor tissue biopsies, utilizing multi-omics approaches, enabled the identification of iCC's intratumor heterogeneity and paved the way for the introduction of novel targeted therapies under the scope of precision medicine. Yet, the unmet need for optimal care of patients with chemo-refractory disease or without targetable mutations still exists. Immunotherapy has provided a paradigm shift in cancer care over the past decade. Currently, immunotherapeutic strategies for the management of iCC are under intense research. Intrinsic factors of the tumor, including programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) status, are simply the tip of the proverbial iceberg with regard to resistance to immunotherapy. Acknowledging the significance of the tumor microenvironment (TME) in both cancer growth and drug response, we broadly discuss about its diverse immune components. We further review the emerging role of immunotherapy in this rare disease, summarizing the results of completed and ongoing phase I-III clinical trials, expounding current challenges and future directions.

SUBMITTER: Fiste O

PROVIDER: S-EPMC8146949 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Surgical Treatment of Intrahepatic Cholangiocarcinoma: Current and Emerging Principles.

Project description:Intrahepatic cholangiocarcinoma (ICC) is a rare, aggressive cancer of the biliary tract. It often presents with locally advanced or metastatic disease, but for patients with early-stage disease, surgical resection with negative margins and portahepatis lymphadenectomy is the standard of care. Recent advancements in ICC include refinement of staging, improvement in liver-directed therapies, clarification of the role of adjuvant therapy based on new randomized controlled trials, and advances in minimally invasive liver surgery. In addition, improvements in neoadjuvant strategies and surgical techniques have enabled expanded surgical indications and reduced surgical morbidity and mortality. However, recurrence rates remain high and more effective systemic therapies are still necessary to improve recurrence-free and overall survival. In this review, we focus on current and emerging surgical principals for the management of ICC including preoperative evaluation, current indications for surgery, strategies for future liver remnant augmentation, technical principles, and the role of neoadjuvant and adjuvant therapies.

| S-EPMC7796337 | biostudies-literature

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

Project description: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.

| S-EPMC9382583 | biostudies-literature

Asbestos and Intrahepatic Cholangiocarcinoma.

Project description:The link between asbestos exposure and the onset of thoracic malignancies is well established. However epidemiological studies have provided evidences that asbestos may be also involved in the development of gastrointestinal tumors, including intrahepatic cholangiocarcinoma (ICC). In line with this observation, asbestos fibers have been detected in the liver of patients with ICC. Although the exact mechanism still remains unknown, the presence of asbestos fibers in the liver could be explained in the light of their translocation pathway following ingestion/inhalation. In the liver, thin and long asbestos fibers could remain trapped in the smaller bile ducts, particularly in the stem cell niche of the canals of Hering, and exerting their carcinogenic effect for a long time, thus inducing hepatic stem/progenitor cells (HpSCs) malignant transformation. In this scenario, chronic liver damage induced by asbestos fibers over the years could be seen as a classic model of stem cell-derived carcinogenesis, where HpSC malignant transformation represents the first step of this process. This phenomenon could explain the recent epidemiological findings, where asbestos exposure seems mainly involved in ICC, rather than extrahepatic cholangiocarcinoma, development.

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Intrahepatic cholangiocarcinoma: current perspectives.

Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy arising from the liver. ICC makes up about 10% of all cholangiocarcinomas. It arises from the peripheral bile ducts within the liver parenchyma, proximal to the secondary biliary radicals. Histologically, the majority of ICCs are adenocarcinomas. Only a minority of patients (15%) present with resectable disease, with a median survival of less than 3 years. Multidisciplinary management of ICC is complicated by large differences in disease course for individual patients both across and within tumor stages. Risk models and nomograms have been developed to more accurately predict survival of individual patients based on clinical parameters. Predictive risk factors are necessary to improve patient selection for systemic treatments. Molecular differences between tumors, such as in the epidermal growth factor receptor status, are promising, but their clinical applicability should be validated. For patients with locally advanced disease, several treatment strategies are being evaluated. Both hepatic arterial infusion chemotherapy with floxuridine and yttrium-90 embolization aim to downstage locally advanced ICC. Selected patients have resectable disease after downstaging, and other patients might benefit because of postponing widespread dissemination and biliary obstruction.

| S-EPMC5328612 | biostudies-literature

Management of Intrahepatic Cholangiocarcinoma.

Project description:Cholangiocarcinoma is a tumor that arises as a result of differentiation of the cholangiocytes and can develop from anywhere in the biliary tree. Subtypes of cholangiocarcinoma are differentiated based on their location in the biliary tree. If diagnosed early these can be resected, but most cases of intrahepatic cholangiocarcinoma present late in the disease course where surgical resection is not an option. In these patients who are poor candidates for resection, a combination of chemotherapy, locoregional therapies like ablation, transarterial chemo and radioembolization, and in very advanced and metastatic disease, external radiation are the available options. These modalities can improve overall disease-free and progression-free survival chances. In this review, we will discuss the risk factors and clinical presentation of intrahepatic cholangiocarcinoma, diagnosis, available therapeutic options, and future directions for management options.

| S-EPMC8198953 | biostudies-literature

microRNA profile of human intrahepatic cholangiocarcinoma: intrahepatic cholangiocarcinoma vs. normal intrahepatic bile duct tissue

Project description:MicroRNA expression profiles were sucessfully contructed in 63 patients with ICC and 9 normal intrahepatic bile ducts using a custom microarray containing probes for 1094 miRNAs and an outcome prediction of miRNA signature was successfully identified for predicting prognosis in ICC.

2015-03-06 | GSE53870 | GEO

Rare DNA Mismatch Repair-Related Protein Loss in Patients with Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma and Their Response to Immunotherapy.

Project description:PurposeThe patients with advanced mismatch repair deficiency (dMMR) cancers can benefit from programmed cell death 1 (PD-1) pathway blockade, regardless of the tumor type. Little is known about the prevalence of dMMR in intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC). This study aimed to assess the mismatch repair (MMR)-related protein expression in patients with ICC and cHCC-CC.Patients and methodsFormalin-fixed, paraffin-embedded tumor specimens were obtained from patients undergoing surgery at the West china Hospital between 2009 and 2017. The immunoreactions for MLH1, MSH2, MSH6, and PMS2 were investigated to determine the MMR status.ResultsA total of 97 patients were evaluated, including 73 ICC patients and 24 cHCC-CC patients. The prevalence of dMMR was only found in two cases of 97 patients (2.06%). Both patients are ICC. In 24 cHCC-CC patients, no dMMR was observed. They did not receive an adjuvant chemotherapy after surgery. At the end of the follow-up, one patient was in a tumor-free state, and the other patient had local recurrence and metastasis. After receiving sintilimumab (an immune checkpoint inhibitor [ICI] for PD- 1), the patient had a partial response.ConclusionDMMR was detected in few patients with ICC and cHCC-CC. Thus, it is not recommended to routinely evaluate the MMR status of patients with ICC or cHCC-CC after surgery, but that of patients with advanced ICC or cHCC-CC should be assessed.

| S-EPMC8183674 | biostudies-literature

Imaged periductal infiltration: Diagnostic and prognostic role in intrahepatic mass-forming cholangiocarcinoma.

Project description:PurposeThis study examines periductal infiltration in intrahepatic mass-forming cholangiocarcinoma (IMCC), focusing on its importance for differentiating hepatic tumors and its influence on post-surgical survival in IMCC patients.MethodsEighty-three consecutive patients with IMCC (n = 43) and liver cancer whose preoperative images showed intrahepatic bile duct dilatation adjacent to the tumor for differential diagnosis from hepatocellular carcinoma (HCC) [n = 21], metastatic liver cancer (MLC) [n = 16] and combined hepatocellular-cholangiocarcinoma (cHCC-CC) [n = 3] were enrolled. CT and MRI findings of simple bile duct compression, imaged periductal infiltration, and imaged intrabiliary growth adjacent to the main tumor were reviewed. Clinicopathological and imaging features were compared in each group. The sensitivity, specificity, and odds ratio were calculated for each imaging finding of IMCC versus the other tumor groups. Overall survival was compared between cases of IMCC with and without imaged periductal infiltration.ResultsSimple bile duct compression and imaged intrabiliary growth were more frequently observed in HCC than in the others (p < 0.0001 and 0.040, respectively). Imaged periductal infiltration was observed more often in histopathologically confirmed large-duct type IMCC than in the small-duct type IMCC (p = 0.034). Multivariable analysis demonstrated that only imaged periductal infiltration (odds ratio, 50.67) was independently correlated with IMCC. Patients with IMCC who had imaged periductal infiltration experienced a poorer prognosis than those without imaged periductal infiltration (p = 0.0034).ConclusionImaged periductal infiltration may serve as a significant marker for differentiating IMCC from other liver cancers. It may also have the potential to predict post-surgical outcomes in patients with IMCC.

| S-EPMC10881313 | biostudies-literature

Image-Guided Local Treatment for Unresectable Intrahepatic Cholangiocarcinoma-Role of Interventional Radiology.

Project description:Intrahepatic cholangiocarcinoma is a highly aggressive malignancy with an increasing incidence in recent years. Prognosis is poor and most patients are not eligible for resection at the time of initial diagnosis due to the anatomic location, inadequate hepatic reserve, limiting comorbidities or metastatic disease. Several locoregional therapies from the field of interventional radiology exist for patients who are not amenable for surgery, or in case of local recurrence as a single treatment modality or combined with systemic treatment. To date, evidence is limited, with most conclusions drawn from single-center studies with small patient cohorts, often treated in the salvage situation or for local recurrence after initial resection. Nevertheless, the results are promising and suggest a survival benefit in selected patients. This narrative review focuses on the use of different locoregional treatment options for intrahepatic cholangiocarcinoma.

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Liver Transplantation for Unresectable Intrahepatic Cholangiocarcinoma: The Role of Sequencing Genetic Profiling.

Project description:Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive primary liver tumor, characterized by a range of different clinical manifestations and by increasing incidence and mortality rates even after curative treatment with radical resection. In recent years, growing attention has been devoted to this disease and some evidence supports liver transplantation (LT) as an appropriate treatment for intrahepatic cholangiocarcinoma; evolving work has also provided a framework for better understanding the genetic basis of this cancer. The aim of this study was to provide a clinical description of our series of patients complemented with Next-Generation Sequencing genomic profiling. From 1999 to 2021, 12 patients who underwent LT with either iCCA or a combined hepatocellular and cholangiocellular carcinoma (HCC-iCCA) were included in this study. Mutations were observed in gene activating signaling pathways known to be involved with iCCA tumorigenesis (KRAS/MAPK, P53, PI3K-Akt/mTOR, cAMP, WNT, epigenetic regulation and chromatin remodeling). Among several others, a strong association was observed between the Notch pathway and tumor size (point-biserial rhopb = 0.93). Our results are suggestive of the benefit potentially derived from molecular analysis to improve our diagnostic capabilities and to devise new treatment protocols, and eventually ameliorate long-term survival of patients affected by iCCA or HCC-iCCA.

| S-EPMC8657183 | biostudies-literature

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