Search

Simple Summary: Rare diseases represent a significant health problem since patients face difficulty obtaining a rapid diagnosis and a proper treatment. An inflammatory pseudotumor of the liver (IPTL) is a rare and benign entity in which reaching a correct preoperative diagnosis can be challenging since it is similar to the worst form of liver cancer, intrahepatic cholangiocarcinoma (ICC). Our paper aims to report our experience and to review the available literature on this topic, thus summarizing previous experiences and central issues to point out a prompt road map of treatment that still needs to be standardized. IPTL is not associated with substantial risk factors and presents with faint symptoms. Imaging data via MRI and CT scan are not specific, thus often requiring ultrasound (US)-guided biopsy. Proper and widely accepted gold standard treatment does not exist; conservative strategies represent an accepted option, while the decision for surgery still exists where there is a suspicion of malignancy. An inflammatory pseudotumor of the liver is a rare tumor-like lesion composed of polymorphous inflammatory cell infiltrates and variable amounts of fibrosis that can often mimic a malignant liver neoplasm. The etiology of inflammatory pseudotumors of the liver is unknown; symptoms are faint and imaging non-specific. Thus, it is often hard to make a diagnosis preoperatively and it is not so rare to over-treat patients with this disease or vice versa. Thus, more profound knowledge is necessary to plan appropriate disease management. We reported our two cases and systematically searched the literature regarding IPTL. We selected articles published in English from four databases, PubMed, Scopus, Web of Science and Google Scholar, and we included only articles with consistent data. Twenty nine papers fulfilling criteria for the review were selected. The analysis of 69 cases published from 1953 confirmed that the risk factors are unclear, the imaging data is not specific, and biopsy is crucial but not so widely used in clinical practice due to the procedure's related risks, and relatively low effectiveness and improvement in imaging analysis. Regarding treatment, surgeons have moved towards a more conservative attitude over the years due to better imaging quality and patient surveillance. However, surgery remains the modality of choice for most cases with an indeterminate diagnosis. Even if an inflammatory pseudotumor of the liver is a benign tumor with a good prognosis, not requiring any treatment in most cases, sometimes it remains challenging to differentiate it from ICC; therefore, there is a solid recommendation to manage this condition with a multidisciplinary team. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver cancer leading to death in 10–15% of cases. In recent years, the iCCA worldwide incidence has been increasing, and research is currently focused on identifying valuable diagnostic biomarkers and developing specific therapies to counteract the disease despite its high heterogeneity. The use of cutting-edge and broad-spectrum applications like omics represents a successful approach to studying the intricate pathobiology of iCCA. In this review, we discuss how both single- and multi-omics studies can pave the way for identifying potential biomarkers, and more importantly, for stratifying iCCA patients. This stratification aims to enhance the therapeutic intervention through personalized medicine (PM). Intrahepatic cholangiocarcinoma (iCCA) is recognized worldwide as the second leading cause of morbidity and mortality among primary liver cancers, showing a continuously increasing incidence rate in recent years. iCCA aggressiveness is revealed through its rapid and silent intrahepatic expansion and spread through the lymphatic system leading to late diagnosis and poor prognoses. Multi-omics studies have aggregated information derived from single-omics data, providing a more comprehensive understanding of the phenomena being studied. These approaches are gradually becoming powerful tools for investigating the intricate pathobiology of iCCA, facilitating the correlation between molecular signature and phenotypic manifestation. Consequently, preliminary stratifications of iCCA patients have been proposed according to their "omics" features opening the possibility of identifying potential biomarkers for early diagnosis and developing new therapies based on personalized medicine (PM). The focus of this review is to provide new and advanced insight into the molecular pathobiology of the iCCA, starting from single- to the latest multi-omics approaches, paving the way for translating new basic research into therapeutic practices. [ABSTRACT FROM AUTHOR]

Simple Summary: Biliary tract cancers, which include cholangiocarcinoma, gallbladder, and ampulla of Vater cancers, are a significant health concern due to their increasing incidence and poor survival rates. Using data from the Rochester Epidemiology Project, this study tracks changes in incidence and survival rates among residents aged 20 and over in Olmsted County, Minnesota from 1976 to 2018. The findings illustrate a rise in overall biliary tract cancers from 6.53 cases to 10.25 cases per 100,000 person-years between 1976 and 2018 (p = 0.004). The incidence of intrahepatic cholangiocarcinoma has significantly increased from 0.25 to 3.93 per 100,000 person-years over the four decades, with a more pronounced increase observed in males, while gallbladder cancer incidence has decreased among women. Despite improvements in median survival times from 4.2 months to 10.8 months over the four decades (p = 0.019), the overall prognosis remains very poor. This study highlights the evolving epidemiology of these cancers and the critical need for enhanced diagnostic and treatment strategies to improve patient outcomes. Biliary tract cancers, including cholangiocarcinoma, gallbladder, and ampulla of Vater cancers, rank second among hepatobiliary cancers, known for their poor prognoses. The United States has witnessed a notable increase in intrahepatic cholangiocarcinoma incidence. This study examines the incidence and survival outcomes of biliary tract cancers in Olmsted County, Minnesota from 1976 to 2018. Using data from the Rochester Epidemiology Project (REP), residents aged 20 and above were analyzed across four eras. Incidence rates were calculated and adjusted for age and sex, and temporal trends were assessed using Poisson regression. Intrahepatic cholangiocarcinoma exhibited a significant escalation in incidence rates over time, while gallbladder cancers showed a decline among women. Median survival times for biliary tract cancers notably improved. These findings confirm the rising incidence of intrahepatic cholangiocarcinoma and suggest improving survival rates. Nevertheless, the overall prognosis for biliary tract cancers remains very poor, emphasizing the continual need for enhanced management strategies and further research. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of intrahepatic cholangiocarcinoma (ICC) depends on tumor biology, morphology, and the high rates of late diagnosis and recurrence after curative-intent surgery, with high heterogeneity. Understanding the molecular landscape of ICC and its clinical implications for treatment and prognosis remains a major challenge. Several attempts have been made to classify molecular ICC subtypes, but they have produced heterogeneous results and need a clear clinical definition. This systematic review examined the evidence for the multi-omics-based classification of ICC to assess its clinical and prognostic significance. Molecular analysis of ICC can assist in decision-making by identifying patients who are suitable for targeted pre- and postoperative chemotherapy. Identifying clinical characteristics associated with specific ICC clusters resulting from multi-omics analysis could help tailor patient management. However, there are logistical, technical, and therapeutic challenges in the routine application of ICC molecular characterization. Identifying clinical characteristics commonly found in specific ICC clusters can help define high-risk ICC subtypes quickly and assist in selecting patients who may benefit the most from molecular profiling in the disease's earlier stages. Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous disease characterized by a dismal prognosis. Various attempts have been made to classify ICC subtypes with varying prognoses, but a consensus has yet to be reached. This systematic review aims to gather relevant data on the multi-omics-based ICC classification. The PubMed, Embase, and Cochrane databases were searched for terms related to ICC and multi-omics analysis. Studies that identified multi-omics-derived ICC subtypes and investigated clinicopathological predictors of long-term outcomes were included. Nine studies, which included 910 patients, were considered eligible. Mean 3- and 5-year overall survival were 25.7% and 19.6%, respectively, for the multi-omics subtypes related to poor prognosis, while they were 70.2% and 63.3%, respectively, for the subtypes linked to a better prognosis. Several negative prognostic factors were identified, such as genes' expression profile promoting inflammation, mutations in the KRAS gene, advanced tumor stage, and elevated levels of oncological markers. The subtype with worse clinicopathological characteristics was associated with worse survival (Ref.: good prognosis subtype; pooled hazard ratio 2.06, 95%CI 1.67–2.53). Several attempts have been made to classify molecular ICC subtypes, but they have yielded heterogeneous results and need a clear clinical definition. More efforts are required to build a comprehensive classification system that includes both molecular and clinical characteristics before implementation in clinical practice to facilitate decision-making and select patients who may benefit the most from comprehensive molecular profiling in the disease's earlier stages. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma (ICCA) is the second most common type of primary liver malignancy after hepatocellular carcinoma (HCC). ICCA is characterized by molecular heterogeneity and a diverse histopathological spectrum. Generally, the prognosis for patients diagnosed with ICCA is poor. Recent advances have improved our understanding of the molecular genetics and histological subtypes of ICCA. An accurate diagnosis of ICCA is important for patient management and prognosis. This review aims to provides an updated overview of the pathology of ICCA, with a particular focus on its molecular genetics, histological subtypes, and the diagnostic approaches necessary to distinguish it from other diseases. Intrahepatic cholangiocarcinoma (ICCA) is a malignant epithelial neoplasm characterized by biliary differentiation within the liver. ICCA is molecularly heterogeneous and exhibits a broad spectrum of histopathological features. It is a highly aggressive carcinoma with high mortality and poor survival rates. ICCAs are classified into two main subtypes: the small-duct type and large-duct types. These two tumor types have different cell origins and clinicopathological features. ICCAs are characterized by numerous molecular alterations, including mutations in KRAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, SAMD4, and EGFR, and FGFR2 fusion. Two main molecular subtypes—inflammation and proliferation—have been proposed. Recent advances in high-throughput assays using next-generation sequencing have improved our understanding of ICCA pathogenesis and molecular genetics. The diagnosis of ICCA poses a significant challenge for pathologists because of its varied morphologies and phenotypes. Accurate diagnosis of ICCA is essential for effective patient management and prognostic determination. This article provides an updated overview of ICCA pathology, focusing particularly on molecular features, histological subtypes, and diagnostic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma is a rare primary liver tumor with a poor prognosis and a 5-year survival rate of 9%. While surgical resection offers the best chance of long-term survival, only a subset of patients will present with resectable disease at presentation, and upwards of 70% of patients experience recurrence following resection. Consequently, systemic therapies play an important role in the management of resectable disease. This review summarizes the approach to resectable intrahepatic cholangiocarcinoma and reviews current evidence from clinical trials regarding systemic and targeted therapies. The management of resectable intrahepatic cholangiocarcinoma remains a challenge due to the high risk of recurrence. Numerous clinical trials have identified effective systemic therapies for advanced biliary tract cancer; however, fewer trials have evaluated systemic therapies in the perioperative period. The objective of this review is to summarize the current recommendations regarding the diagnosis, surgical resection, and systemic therapy for anatomically resectable intrahepatic cholangiocarcinoma. Our review demonstrates that surgical resection with microscopic negative margins and lymphadenectomy remains the cornerstone of treatment. High-level evidence regarding specific systemic therapies for use in resectable intrahepatic cholangiocarcinoma remains sparse, as most of the evidence is extrapolated from trials involving heterogeneous tumor populations. Targeted therapies are an evolving practice for intrahepatic cholangiocarcinoma with most evidence coming from phase II trials. Future research is required to evaluate the use of neoadjuvant therapy for patients with resectable and borderline resectable disease. [ABSTRACT FROM AUTHOR]

Simple Summary: The noninvasive differentiation of hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC) remains challenging. In recent years, the number of studies on the application of radiomics in liver cancer has grown dramatically. However, there have been very few studies on the differentiation of HCC from ICC based on multisequence magnetic resonance imaging (MRI) radiomics. This study aimed to investigate the efficacy of a radiomics model based on pretherapeutic fat suppression T2-weighted imaging (FS-T2WI) and dynamic-contrast-enhanced MRI (DCE-MRI) features obtained from the arterial phase (AP) and portal venous phase (PVP) for noninvasively differentiating HCC from ICC. The purpose of this study was to investigate the efficacy of magnetic resonance imaging (MRI) radiomics in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC). The clinical and MRI data of 129 pathologically confirmed HCC patients and 48 ICC patients treated at the Affiliated Hospital of North Sichuan Medical College between April 2016 and December 2021 were retrospectively analyzed. The patients were randomly divided at a ratio of 7:3 into a training group of 124 patients (90 with HCC and 34 with ICC) and a validation group of 53 patients (39 with HCC and 14 with ICC). Radiomic features were extracted from axial fat suppression T2-weighted imaging (FS-T2WI) and axial arterial-phase (AP) and portal-venous-phase (PVP) dynamic-contrast-enhanced MRI (DCE-MRI) sequences, and the corresponding datasets were generated. The least absolute shrinkage and selection operator (LASSO) method was used to select the best radiomic features. Logistic regression was used to establish radiomic models for each sequence (FS-T2WI, AP and PVP models), a clinical model for optimal clinical variables (C model) and a joint radiomics model (JR model) integrating the radiomics features of all the sequences as well as a radiomics–clinical model combining optimal radiomic features and clinical risk factors (RC model). The performance of each model was evaluated using the area under the receiver operating characteristic curve (AUC). The AUCs of the FS-T2WI, AP, PVP, JR, C and RC models for distinguishing HCC from ICC were 0.693, 0.863, 0.818, 0.914, 0.936 and 0.977 in the training group and 0.690, 0.784, 0.727, 0.802, 0.860 and 0.877 in the validation group, respectively. The results of this study suggest that MRI-based radiomics may help noninvasively differentiate HCC from ICC. The model integrating the radiomics features and clinical risk factors showed a further improvement in performance. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma (ICC) is a liver cancer with a poor prognosis, which is often not resectable at diagnosis. The search for novel effective treatments for ICC continues, but without much progress. One of the options is treatment with small particles carrying radionuclides yttrium-90 or holmium-166, which are delivered to the tumor through the artery to irradiate it locally. This allows for fewer side effects than systemic treatments while achieving good tumor control. While substantial evidence has accumulated for yttrium-90 radiotherapy, much less evidence is available for the more recent holmium-166. This work describes a series of seven patients with ICC treated with holmium-166 transarterial radiotherapy. Most of the patients achieved good tumor control after treatment and had no severe adverse events, highlighting the tolerability of the therapy. In cases of palliative intent of the treatment, this approach can help improve the quality of life and prolong the remaining years of life. Background: Transarterial radioembolization (TARE) is used to treat primary and secondary malignancies in the liver that are not amenable to curative resection. Accumulating evidence demonstrates the efficacy and safety of TARE with yttrium-90 (90Y), which is the most widely used radionuclide for TARE, and later with holmium-166 (166Ho) for various indications. However, the safety and efficacy of 166Ho TARE in patients with intrahepatic cholangiocarcinoma (ICC) remains to be studied. Methods: This was a retrospective case series study of seven consecutive patients with ICC who were treated with 166-Ho-TARE in our center. We recorded the clinical parameters and outcomes of the TARE procedures, the tumor response according to mRECIST, subsequent treatments, and adverse events. Results: Three out of the seven patients had a partial or complete response. Two patients had stable disease after the first TARE procedure, and two of the patients (one with a complete response, and one with stable disease) were alive at the time of analysis. No serious adverse events related to the procedure were recorded. Conclusions: This is the first case series reporting the safety and tumor response outcomes of 166Ho-TARE for ICC. The treatment demonstrated its versatility, allowing for reaching a high tumor dose, which is important for improving tumor response and treating patients in a palliative setting, where safety and the preservation of quality of life are paramount. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of intrahepatic cholangiocarcinoma continues to rise, but survival remains dismal. Because malignancy often remains clinically indolent, treatment of the neoplasm becomes challenging. In advanced disease, locoregional therapies may be employed as a means of reducing toxicity and gaining disease control. A thorough understanding of these locoregional therapies will allow for optimal, individualized treatment. The intent of this review is to describethe role of intra-arterial therapies in the management of intrahepatic cholangiocarcinoma. Intrahepatic cholangiocarcinoma (ICC) is a rare disease with a rising incidence. While surgical resection is the only curative option, the disease process is often identified in advanced stages, as this malignancy often remains clinically silent in early development. Only one-third of patients are eligible for resection at the time of diagnosis. For patients who cannot undergo resection, intra-arterial therapies are reasonable palliative treatment options; in rare occasions, these may be bridging therapies, as well. The premise of bland embolization and most chemoembolization intra-arterial therapies is that the arterial supply of the tumor is occluded to induce tumor necrosis, while radioembolization utilizes the arterial flow of the tumor to deliver radiation therapy. In this review, we discuss the use of transarterial embolization, transarterial chemoembolization, and selective internal radiation therapy for the treatment of ICC. Phase III randomized controlled clinical trials are difficult to tailor to this extremely rare and aggressive disease, but ultimately, further investigation should be pursued to define the patient population that will derive the greatest benefit from each modality. [ABSTRACT FROM AUTHOR]

Simple Summary: While indocyanine green (ICG) fluorescence imaging has widely been used as an intraoperative navigation tool, its efficacy for visualization of hepatic tumors remains to be clarified, especially in robot-assisted hepatectomy (RAH). In our present study, fluorescence imaging identified tumors on hepatic surfaces before hepatic transection in 26/31 tumors. In eight tumors, fluorescence signals were detected from hepatic raw surfaces during parenchymal dissection, enabling surgeons to adjust transection planes to determine surgical margins. As a result, pathological examinations found negative surgical margins at the site of dissected hepatic parenchyma in all tumors identified using fluorescence imaging. On the contrary, a positive surgical margin surrounding dissected hepatic parenchyma was observed in one of two patients in whom ICG was contraindicated. ICG fluorescence imaging enables the identification of hepatic tumors easily even in the setting of RAH, which may be useful for determining surgical margins. The efficacy of indocyanine green (ICG) fluorescence imaging for visualizing hepatic tumors in robot-assisted hepatectomy (RAH) should be validated. This study included 30 consecutive patients with 33 collective tumors who underwent RAH. ICG was administered at a dose of 0.5 mg/kg before surgery. ICG fluorescence imaging was performed intraoperatively. In total, 28 patients with a combined total of 31 tumors underwent ICG fluorescence imaging. Further, 26 (84%) tumors were identified on hepatic surfaces prior to hepatic transection. The fluorescence signals of eight tumors were detected on hepatic raw surfaces during parenchymal dissection, thereby enabling surgeons to adjust the transection planes to ensure appropriate surgical margins. One patient with intrahepatic cholangiocarcinoma tested positive for cancer cells at the dissected stump of the bile duct. However, in all patients in whom ICG fluorescence imaging was used, negative surgical margins were achieved at the site of the dissected hepatic parenchyma. On the other hand, one of two patients with ICG contraindications had a positive surgical margin surrounding the dissected hepatic parenchyma. The median operative time and volume of blood loss were 259 (range: 124–594) min and 150 (range: 1–1150) mL, respectively. ICG fluorescence imaging facilitates the easy identification of hepatic tumors, even in RAH. Hence, it can be useful for confirming appropriate surgical margins. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma is the second most common primary liver malignancy after hepatocellular carcinoma and accounts for 20% of biliary tract cancers. The incidence of biliary tract cancer has been increasing in recent years, and many patients with biliary tract cancer are diagnosed as unresectable, and, even if resectable, the survival rate is very low. From 2010 to 2021, systemic combination therapy with gemcitabine and cisplatin was the standard therapy for biliary tract cancer. In 2022, the first immunotherapy durvalumab was approved to be added to this combination. As with other solid tumors, immune-based therapies for patients with advanced biliary tract cancer have been shown to have promising outcomes. We discuss the efficacy and safety of these therapies and consider new standards of care. Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10–15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC. [ABSTRACT FROM AUTHOR]

Simple Summary: The diagnosis of intrahepatic cholangiocarcinoma in a cirrhotic liver is considered a contradiction for transplantation in Germany, as well as many other international transplantation programs. The aim of our retrospective study was to evaluate the long-term outcomes of patients with incidental combined hepatocellular- and cholangiocarcinoma and sole intrahepatic cholangiocarcinomas after liver transplantation. Between January 2010 and December 2022, iCCA was found in eight patients post-transplant. We confirmed high overall survival and low recurrence rates after liver transplantation. It can be stated that liver transplantation in the case of combined hepatocellular carcinoma and sole intrahepatic cholangiocarcinoma presents a possible curative therapy option. Background: Data about liver transplantation for mixed tumors from hepatocellular carcinoma to cholangiocarcinoma are limited. Furthermore, the diagnosis of intrahepatic cholangiocarcinoma or combined tumors in a cirrhotic liver is considered a contraindication for transplantation. Our aim was to evaluate the long-term outcomes of patients with incidental cholangiocarcinoma or combined tumors after liver transplantation. Methods: In our descriptive analysis, data were evaluated from all patients since 2010 who received a liver transplant due to an assumed hepatocellular carcinoma at Jena University Hospital. Survival rates were determined using the Kaplan–Meier method. Results: Between January 2010 and December 2022, an incidental intrahepatic cholangiocarcinoma was found in eight patients post-transplant. Four combined hepatocellular and cholangiocarcinoma and four sole intrahepatic cholangiocarcinomas were found. A recurrence through distant metastases from combined hepatocellular- and cholangiocarcinoma was found in one patient at one year after transplantation. Another patient developed a pulmonary primary tumor independently one year post-transplant. The recurrence rate was at 14.3%. While two patients died, the 1- and 5-year overall survival rates post-transplant were 87.5% and 75%, respectively. Conclusion: Patients with intrahepatic cholangiocarcinoma or combined hepatocellular- and cholangiocarcinoma could profit from liver transplantation. [ABSTRACT FROM AUTHOR]

Simple Summary: Contrast imaging techniques play a pivotal role in the diagnosis and management of Intrahepatic cholangiocarcinoma (iCCA). There is an increasing interest in the specific imaging features which can predict tumor behavior or histologic subtypes. Intrahepatic cholangiocarcinoma (iCCA) represents the second most common liver cancer after hepatocellular carcinoma, accounting for 15% of primary liver neoplasms. Its incidence and mortality rate have been rising during the last years, and total new cases are expected to increase up to 10-fold during the next two or three decades. Considering iCCA's poor prognosis and rapid spread, early diagnosis is still a crucial issue and can be very challenging due to the heterogeneity of tumor presentation at imaging exams and the need to assess a correct differential diagnosis with other liver lesions. Abdominal contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) plays an irreplaceable role in the evaluation of liver masses. iCCA's most typical imaging patterns are well-described, but atypical features are not uncommon at both CT and MRI; on the other hand, contrast-enhanced ultrasound (CEUS) has shown a great diagnostic value, with the interesting advantage of lower costs and no renal toxicity, but there is still no agreement regarding the most accurate contrastographic patterns for iCCA detection. Besides diagnostic accuracy, all these imaging techniques play a pivotal role in the choice of the therapeutic approach and eligibility for surgery, and there is an increasing interest in the specific imaging features which can predict tumor behavior or histologic subtypes. Further prognostic information may also be provided by the extraction of quantitative data through radiomic analysis, creating prognostic multi-parametric models, including clinical and serological parameters. In this review, we aim to summarize the role of contrast-enhanced imaging in the diagnosis and management of iCCA, from the actual issues in the differential diagnosis of liver masses to the newest prognostic implications. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer continues to exhibit increasing incidence and mortality worldwide. Subsequently, there has been a concomitant effort to development novel therapeutics that effectively target and treat these malignancies. This paper aims to provide a thorough review of the available immunotherapy treatments that target liver cancer, with a specific focus on the role and potential therapeutic strategies available to the interventional radiologist. The underlying biochemical and molecular mechanisms underlying these diseases are discussed to highlight the specific targets for immunotherapy, the clinical efficacy and safety of available pharmaceutical treatments are analyzed, and future advancements in the field, such as combination therapies and personalized medicine, are explored as they pertain to the immunotherapy of liver cancer. Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise in minimally invasive locoregional therapy, as the bulk of these tumors are usually in the liver. The aim of this review is to highlight the immunological therapeutic targets for primary liver cancers, the available immune-based approaches, and the contributions that interventional radiology can provide in the care of these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma is an aggressive primary liver cancer originating in the intrahepatic bile ducts. While surgical resection is the only curative treatment, many patients present with locally advanced, unresectable, or metastatic disease, and few are candidates for curative-intent resection. In this review, we examine locoregional therapy approaches and summarize the current literature. Current locoregional therapies include thermal ablation, transarterial chemoembolization, transarterial radioembolization, external beam radiotherapy, stereotactic body radiotherapy, hepatic arterial infusion of chemotherapy, irreversible electroporation, and brachytherapy. These therapies are most often offered to patients with unresectable primary or recurrent intrahepatic cholangiocarcinoma, and studies on each modality have shown these locoregional approaches to be effective for prolonging overall survival. The findings of this review also further inform the need for future research regarding the efficacy of these treatments in comparison to each other due to the limited literature on optimal treatment strategies. Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, and surgical resection (SR) offers the only potential for cure. Unfortunately, only a small proportion of patients are eligible for resection due to locally advanced or metastatic disease. Locoregional therapies (LRT) are often used in unresectable liver-only or liver-dominant ICC. This review explores the role of these therapies in the treatment of ICC, including radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), external beam radiotherapy (EBRT), stereotactic body radiotherapy (SBRT), hepatic arterial infusion (HAI) of chemotherapy, irreversible electroporation (IE), and brachytherapy. A search of the current literature was performed to examine types of LRT currently used in the treatment of ICC. We examined patient selection, technique, and outcomes of each type. Overall, LRTs are well-tolerated in the treatment of ICC and are effective in improving overall survival (OS) in this patient population. Further studies are needed to reduce bias from heterogenous patient populations and small sample sizes, as well as to determine whether certain LRTs are superior to others and to examine optimal treatment selection. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognostic impact of intrahepatic lymphatic vessel invasion (LVI) in liver cancer has rarely been reported. We sought to clarify the prognostic impact of intrahepatic lymphatic system involvement in liver cancer. Tumor-associated lymphangiogenesis reportedly correlates with prognosis after HCC resection. A meta-analysis showed that overall survival was poorer in patients with positive LVI than with negative LVI after resection of ICC and colorectal liver metastasis. Lymphangiogenesis was also reported to predict unfavorable prognosis in ICC. A few reports showed correlations between LVI/lymphangiogenesis and LNM in liver cancer. LVI and lymphangiogenesis showed worse prognostic impacts for liver cancer than their absence, but further study is needed. Although several prognosticators, such as lymph node metastasis (LNM), were reported for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the prognostic impact of intrahepatic lymphatic vessel invasion (LVI) in liver cancer has rarely been reported. We sought to clarify the prognostic impact of intrahepatic lymphatic system involvement in liver cancer. We systematically reviewed retrospective studies that described LVI and clinical outcomes of liver cancer and also included studies that investigated tumor-associated lymphangiogenesis. We conducted a meta-analysis using RevMan software (version 5.4.1; Cochrane Collaboration, Oxford, UK). The prognostic impact of intrahepatic LVI in HCC was not reported previously. However, tumor-associated lymphangiogenesis reportedly correlates with prognosis after HCC resection. The prognostic impact of intrahepatic LVI was reported severally for ICC and a meta-analysis showed that overall survival was poorer in patients with positive LVI than with negative LVI after resection of ICC. Lymphangiogenesis was also reported to predict unfavorable prognosis in ICC. Regarding colorectal liver metastases, LVI was identified as a poor prognosticator in a meta-analysis. A few reports showed correlations between LVI/lymphangiogenesis and LNM in liver cancer. LVI and lymphangiogenesis showed worse prognostic impacts for liver cancer than their absence, but further study is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Biliary tract cancers (BTCs) are a rare pathology. In the era of precision oncology, the development of next-generation sequencing (NGS) allowed a better understanding of molecular differences between each tumor. Alterations in genes such as the FGFR, HER2, IDH1, and BRAF, result in cancer development, growth, and proliferation. Recent drug development allowed for the use of medications that can target these alterations and inhibit cancer progression. Additionally, the understanding of how the immune system interacts with cancer cells also resulted in the use of immunotherapy in this difficult scenario, although we still do not know how to select the patients with a higher chance of response. Here, we review the most recent data regarding targeted treatment and immunotherapy in the scenario of BTC treatment, discussing not only the role that these medications have in modern oncology, but also the future perspectives for this challenging disease. Biliary tract cancers (BTCs) are a rare pathology and can be divided into four major subgroups: intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and gallbladder cancer. In the era of precision oncology, the development of next-generation sequencing (NGS) allowed a better understanding of molecular differences between these subgroups. Thus, the development of drugs that can target these alterations and inhibit the abnormal pathway activation has changed the prognosis of BTC patients. Additionally, the development of immune checkpoint inhibitors and a better understanding of tumor immunogenicity led to the development of clinical trials with immunotherapy for this scenario. The development of biomarkers that can predict how the immune system acts against the tumor cells, and which patients benefit from this activation, are urgently needed. Here, we review the most recent data regarding targeted treatment and immunotherapy in the scenario of BTC treatment, while also discussing the future perspectives for this challenging disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Radioembolization is a locoregional therapy used in primary liver malignancies with different applications depending on the treatment goal. The aim of this retrospective study was to evaluate postoperative and long-term survival outcomes of patients with unresectable or high biological risk HCC and ICC treated with RE that were finally rescued to liver surgery with curative intent. In a cohort of 34 patients, we assessed that liver resection and transplantation after RE seem safe and feasible with adequate short-term outcomes. Moreover, long-term outcomes after RE and LR were optimal, with a 10-year OS rate greater than 50% for HCC and ICC patients. On the other hand, the 10-year OS rates from RE were also greater than 50% for patients with HCC downstaged or bridged to LT. Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. Methods: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005–2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. Results: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien–Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. Conclusion: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Mixed hepatocellular cholangiocarcinoma (mHC-CC) is a very rare tumor and data on its outcome after resection are scarce. The aim of this retrospective study was to compare recurrence and survival after surgery of mixed tumors with data from patients with pure hepatocellular (HCC) or intrahepatic cholangiocarcinoma (ICC). The most striking result was that mHC-CC showed a long-term outcome after resection comparable to ICC. Resection of non-cirrhotic HCC was associated with the longest survival, followed by HCC in cirrhosis. A small group of patients who underwent orthotopic liver transplant for mHC-CC had the best long-term outcome. The cholangiocarcinoma component of mHC-CC seems to be the defining outcome. Transplant within the Milan criteria might be a feasible option. Background: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy, followed by intrahepatic cholangiocarcinoma (ICC). In addition, there is a mixed form for which only limited data are available. The aim of this study was to compare recurrence and survival of the mixed form within the cohorts of patients with HCC and ICC from a single center. Methods: Between January 2008 and December 2020, all patients who underwent surgical exploration for ICC, HCC, or mixed hepatocellular cholangiocarcinoma (mHC-CC) were included in this retrospective analysis. The data were analyzed, focusing on preoperative and operative details, histological outcome, and tumor recurrence, as well as overall and recurrence-free survival. Results: A total of 673 surgical explorations were performed, resulting in 202 resections for ICC, 344 for HCC (225 non-cirrhotic HCC, ncHCC; 119 cirrhotic HCC, cHCC), and 14 for mHC-CC. In addition, six patients underwent orthotopic liver transplant (OLT) in the belief of dealing with HCC. In 107 patients, tumors were irresectable (resection rate of 84%). Except for the cHCC group, major or even extended liver resections were required. Vascular or visceral extensions were performed regularly. Overall survival (OS) was highly variable, with a median OS of 17.6 months for ICC, 26 months for mHC-CC, 31.8 months for cHCC, and 37.2 months for ncHCC. Tumor recurrence was common, with a rate of 45% for mHC-CC, 48.9% for ncHCC, 60.4% for ICC, and 67.2% for cHCC. The median recurrence-free survival was 7.3 months for ICC, 14.4 months for cHCC, 16 months for mHC-CC, and 17 months for ncHCC. The patients who underwent OLT for mHC-CC showed a median OS of 57.5 and RFS of 56.5 months. Conclusions: mHC-CC has a comparable course and outcome to ICC. The cholangiocarcinoma component seems to be the dominant one and, therefore, may be responsible for the prognosis. 'Accidental' liver transplant for mHC-CC within the Milan criteria offers a good long-term outcome. This might be an option in countries with no or minor organ shortage. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive malignancy, and its incidence is on the rise worldwide. Surgical resection is the only curative treatment of ICC. The various aspects of surgical management of ICC are discussed in this review. Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive malignancy. It originates from the bile ducts and is the second most common primary cancer of the liver. Surgery is considered the only curative treatment of ICC, offering the best chance for long-term survival. The purpose of this article is to review the available literature on ICC, with a focus on the various aspects of the surgical care in this potentially lethal malignancy. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated recent trends in liver cancer incidence and survival in Italy (2003–2017) based on data from 13 cancer registries covering 21% of the national population. The incidence of total liver cancer and hepatocellular carcinoma (HCC) decreased significantly for both sexes. Intrahepatic cholangiocarcinoma (ICC) followed an opposite trend. The risk of HCC saw a peak for people born around 1930 and another, more moderate peak for those born in the late 1950s. Men and women exhibited comparable improvements in both early and mid-term (conditional) net survival from HCC. The uptrend in survival from ICC was less pronounced. The opposite incidence trends of HCC and ICC confirm a pattern previously observed in other populations. The generalised, albeit slow, improvement in survival from HCC indicates a trend towards an earlier detection coupled with improvements in treatments. (1) Background: Liver cancer in Italy is characterised by one of the highest incidence rates worldwide outside of Asia coupled with comparatively favourable survival figures. The objective of this study was to evaluate the most recent epidemiologic trends of the disease. (2) Methods: Thirteen cancer registries covering a population of about 12,740,000 (21% of the national population) made available the records of 35,574 cases registered between 2003 and 2017. Trends in age-standardised (Europe 2013) incidence rates were analysed using the results of age–drift models. Trends in survival were analysed using 1-year, 2-year, 5-year and 10-year net survival (NS) and 5|1-year and 5|2-year conditional NS. (3) Results: Over the study period, the average annual incidence rates per 100,000 persons were 29.4 (men) and 9.4 (women) for total liver cancer; 14.6 and 3.5 for hepatocellular carcinoma (HCC); 1.8 and 1.1 for intrahepatic cholangiocarcinoma (ICC); and 13.0 and 4.8 for the 'other liver cancer types' group. The incidence of total liver cancer and HCC decreased significantly for both sexes. For total liver cancer, the estimated average annual percent change was −1.6% among men and −2.1% among women. For HCC, the change was −1.3% among men and −2.7% among women. ICC followed an opposite trend. For men, the risk of HCC had two peaks, one in the birth cohorts of 1928 and 1933 and another, more moderate peak in the cohort of 1958. Men and women exhibited comparable improvements in both early and mid-term conditional NS from HCC. In 2013–2017, 5-year NS was 28.9% (95% CI: 27.3%; 30.6%) for men and 30.1% (95% CI: 26.9%; 33.5%) for women. The uptrend in survival from ICC was less pronounced and was weakly significant, with a 5-year NS in 2013-2017 of 13.9% (95% CI: 10.8%; 17.3%) for men and 17.4% (95% CI: 13.5%; 21.7%) for women. (4) Conclusions: The opposite incidence trends of HCC and ICC confirm a pattern observed in other populations. The generalised, albeit slow, improvement in survival from HCC indicates a trend towards earlier detection coupled with improvements in treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton beam therapy (PBT) has the potential to improve local tumor control and subsequently improve survival of patients with inoperable or recurrent intrahepatic cholangiocarcinoma (IHCC); however, studies on PBT in patients with IHCC are still limited. This study evaluated the efficacy and safety of hypofractionated PBT in IHCC patients with inoperable or recurrent disease. Our findings demonstrated that hypofractionated PBT was considered tolerable and safe and offers a high rate of local tumor control and promising survival in patients with IHCC. In addition, the survival outcomes in selected patients with localized disease treated with hypofractionated PBT were comparable to those of surgical resection. Further large-scale studies are warranted to confirm these findings. Forty-seven patients with intrahepatic cholangiocarcinoma (IHCC) who received proton beam therapy (PBT) were analyzed to evaluate the clinical efficacy and safety of hypofractionated PBT in patients with inoperable or recurrent IHCC. The median prescribed dose of PBT was 63.3 GyE (range: 45–80 GyE) in 10 fractions, and the median duration of follow-up in all the patients was 18.3 months (range: 2.4–89.9 months). Disease progression occurred in 35 of the 47 (74.5%) patients; local, intrahepatic, and extrahepatic progression occurred in 5 (10.6%), 20 (42.6%), and 29 (61.7%) patients, respectively. The 2-year freedom from local progression (FFLP), progression-free survival (PFS), overall survival (OS) rates, and median time of OS were 86.9% (95% confidence interval [CI], 74.4–99.4%), 16.8% (95% CI, 4.3–29.3%), 42.7% (95% CI, 28.0–57.4%), and 21.9 months (95% CI, 16.2–28.3 months), respectively; grade ≥ 3 adverse events were observed in four (8.5%) patients. In selected patients with localized disease (no viable tumors outside of the PBT sites), the median time of OS was 33.8 months (95% CI, 5.4–62.3). These findings suggest that hypofractionated PBT is safe and could offer a high rate of FFLP and promising OS in patients with inoperable or recurrent IHCC. [ABSTRACT FROM AUTHOR]

Simple Summary: We were able to stratify intrahepatic cholangiocellular carcinoma (ICC) patients who underwent hepatectomy into three risk groups using a classification and regression tree (CART) model for recurrence-free survival (RFS) and overall survival (OS). CART analysis, using results from the multivariate analysis, revealed decision trees for RFS and OS based on machine learning using preoperative serum markers. These three risk classifications using preoperative noninvasive prognostic factors could predict prognosis for ICC. These risk classifications are simple and easy to understand and can be clinically applied. Accurate risk stratification selects patients who are expected to benefit most from surgery. This retrospective study enrolled 225 Japanese patients with intrahepatic cholangiocellular carcinoma (ICC) who underwent hepatectomy between January 2009 and December 2020 and identified preoperative blood test biomarkers to formulate a classification system that predicted prognosis. The optimal cut-off values of blood test parameters were determined by ROC curve analysis, with Cox univariate and multivariate analyses identifying prognostic factors. Risk classifications were established using classification and regression tree (CART) analysis. CART analysis revealed decision trees for recurrence-free survival (RFS) and overall survival (OS) and created three risk classifications based on machine learning of preoperative serum markers. Five-year rates differed significantly (p < 0.001) between groups: 60.4% (low-risk), 22.8% (moderate-risk), and 4.1% (high-risk) for RFS and 69.2% (low-risk), 32.3% (moderate-risk), and 9.2% (high-risk) for OS. No difference in OS was observed between patients in the low-risk group with or without postoperative adjuvant chemotherapy, although OS improved in the moderate group and was prolonged significantly in the high-risk group receiving chemotherapy. Stratification of patients with ICC who underwent hepatectomy into three risk groups for RFS and OS identified preoperative prognostic factors that predicted prognosis and were easy to understand and apply clinically. [ABSTRACT FROM AUTHOR]

Simple Summary: Radioembolization (RE) for intrahepatic cholangiocarcinoma (ICC) is a viable treatment option. As the overall survival (OS) is subject to considerable variance, proper patient selection is of the utmost importance. The current study elucidated overall survival (time from treatment to the patient's death) in 39 patients after RE in ICC. Out of all the investigated parameters, we identified three pre-therapeutic parameters which were able to predict both OS and patient prognosis by means of a score. More specifically, stratification of the patient cohort by pre-therapeutic GGT, clinical performance status (ECOG) and albumin resulted in significant differences regarding OS (0 risk factors, 15.3 months; 1 risk factor, 7.6 months; ≥2 risk factors, 1.8 months, respectively). Consequently, implementation of this proposed prognostic score may facilitate pre-therapeutic identification of patients who could benefit from RE in ICC. Radioembolization (RE) is a viable therapy option in patients with intrahepatic cholangiocarcinoma (ICC). This study delineates a prognostic score regarding overall survival (OS) after RE using routine pre-therapeutic parameters. A retrospective analysis of 39 patients (median age, 61 [range, 32–82] years; 26 females, 13 males) with ICC and 42 RE procedures was conducted. Cox regression for OS included age, ECOG, hepatic and extrahepatic tumor burden, thrombosis of the portal vein, ascites, laboratory parameters and dose reduction due to hepatopulmonary shunt. Median OS after RE was 8.0 months. Using univariable Cox, ECOG ≥ 1 (hazard ratio [HR], 3.8), AST/ALT quotient (HR, 1.86), high GGT (HR, 1.002), high CA19-9 (HR, 1.00) and dose reduction of 40% (HR, 3.8) predicted shorter OS (each p < 0.05). High albumin predicted longer OS (HR, 0.927; p = 0.045). Multivariable Cox confirmed GGT ≥ 750 [U/L] (HR, 7.84; p < 0.001), ECOG > 1 (HR, 3.76; p = 0.021), albumin ≤ 41.1 [g/L] (HR, 3.02; p = 0.006) as a three-point pre-therapeutic prognostic score. More specifically, median OS decreased from 15.3 months (0 risk factors) to 7.6 months (1 factor) or 1.8 months (≥2 factors; p < 0.001). The proposed score may aid in improved pre-therapeutic patient identification with (un-)favorable OS after RE and facilitate the balance between potential life prolongation and overaggressive patient selection. [ABSTRACT FROM AUTHOR]

Simple Summary: The long-term outcome of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) is not well studied. Although the importance of the resection margin depth is clear, we aimed to clarify the impact of the R1 resection, by focusing on the outcomes between R0 resection and the two R1 types. The R1par resection presented a DFS and an OS intermediate between R0 and R1vasc. It appeared that a R1vasc resection should be avoided in patients with iCCA because it did not provide satisfactory oncological outcomes. Further studies could help to understand the best therapeutic procedure for these patients and the role of neo-adjuvant therapies in case of foreseeable R1vasc resection. Background: to date, long-term outcomes of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) have been examined in only one study which did not find significant difference. Patients and Methods: we analyzed consecutive patients who underwent iCCA resection between 2000 and 2019 in two tertiary French medical centers. We report overall survival (OS) and disease-free-survival (DFS). Univariate and multivariate analyses were performed to determine associated factors. Results: 195 patients were analyzed. The number of R0, R1par and R1vasc patients was 128 (65.7%), 57 (29.2%) and 10 (5.1%), respectively. The 1- and 2-year OS rates in the R0, R1par and R1vasc groups were 83%, 87%, 57% and 69%, 75%, 45%, respectively (p = 0.30). The 1- and 2-year DFS rates in the R0, R1par and R1vasc groups were 58%, 50%, 30% and 43%, 28%, 10%, respectively (p = 0.019). Resection classification (HR 1.56; p = 0.003) was one of the independent predictors of DFS in multivariate analysis. Conclusions: the survival outcomes after R1par resection are intermediate to those after R0 or R1vasc resection. R1vasc resection should be avoided in patients with iCCA as it does not provide satisfactory oncological outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma (ICC) is a primary liver cancer that currently has limited treatment options and an overall poor prognosis. Evidence-based guidelines for the management of resectable ICC are lacking. We investigated three treatment strategies for resectable ICC using a large cancer registry and compared their use and oncologic outcomes. Our findings suggest a benefit of both neoadjuvant and adjuvant therapy for patients with high-risk resectable ICC. Prospective and randomized studies are needed to better define patients who may benefit from systemic therapy and to clarify the most appropriate sequencing of treatment for resectable ICC. Limited evidence-based management guidelines for resectable intrahepatic cholangiocarcinoma (ICC) currently exist. Using a large population-based cancer registry; the utilization rates and outcomes for patients with clinical stages I-III ICC treated with neoadjuvant chemotherapy (NAT) in relation to other treatment strategies were investigated, as were the predictors of treatment regimen utilization. Oncologic outcomes were compared between treatment strategies. Amongst 2736 patients, chemotherapy utilization was low; however, NAT use increased from 4.3% to 7.2% (p = 0.011) over the study period. A higher clinical stage was predictive of the use of NAT, while higher pathologic stage and margin-positive resections were predictive of the use of adjuvant therapy (AT). For patients with more advanced disease, the receipt of NAT or AT was associated with significantly improved survival compared to surgery alone (cStage II, p = 0.040; cStage III, p = 0.003). Furthermore, patients receiving NAT were more likely to undergo margin-negative resections compared to those treated with AT (72.5% vs. 62.6%, p = 0.027), despite having higher-risk tumors. This analysis of treatment strategies for resectable ICC suggests a benefit for systemic therapy. Prospective and randomized studies evaluating the sequencing of treatments for patients with high-risk resectable ICC are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Only about 15% of intrahepatic cholangiocarcinoma (ICC) patients meet the criteria for resection at the time of diagnosis. For patients with advanced and/or metastatic disease, the development of novel therapeutic strategies is urgently needed. The aim of our study was to identify possible novel therapeutic targets and drugs for ICC by using transcriptomic profiles from the Gene Expression Omnibus databases and The Cancer Genome Atlas. The weighted co-expression gene network was constructed to screen hub genes. Potential drug candidates with promise in the treatment of ICC were identified by analyzing key protein–protein interaction (PPI) networks of the hub genes to identify potential interacting drugs based on the Connectivity Map database. Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy, and there is a need for effective systemic therapies. Gene expression profile-based analyses may allow for efficient screening of potential drug candidates to serve as novel therapeutics for patients with ICC. The RNA expression profile of ICC and normal biliary epithelial cells were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Function annotation and enrichment pathway analyses of the differentially expressed genes (DEGs) were finished using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. A weighted gene co-expression network (WGCN) was constructed by WGCN analysis (WGCNA). Key genes from the DEGs and co-expression gene modules were analyzed to generate a protein–protein interaction (PPI) network. The association between the top 10 screened hub genes and the overall and disease-free survival of ICC patients was examined. The Connectivity Map (cMap) analysis was performed to identify possible drugs for ICC using hub genes. A total of 151 key genes were selected from the overlapping genes of 1287 GSE-DEGs, 8183 TCGA-DEGs and 1226 genes in the mixed modules. A total of 10 hub genes of interest (CTNNB1, SPP1, COL1A2, COL3A1, SMAD3, SRC, VCAN, PKLR, GART, MRPS5) were found analyzing protein–protein interaction. Using the cMap, candidate drugs screened with potential efficacy for ICC included three tyrosine kinase inhibitors (dasatinib, NVP-BHG712, tivantinib), two cannabinoid receptor agonists (palmitoylethanolamide, arachidonamide), two antibiotics (moxifloxacin, amoxicillin), one estrogen receptor agonist (levonorgestrel), one serine/threonine protein kinase inhibitor (MK-2206) and other small molecules. Key genes from network and PPI analysis allowed us to identify potential drugs for ICC. The identification of novel gene expression profiles and related drug screening may accelerate the identification of potential novel drug therapies for ICC. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. A newly invented PRE-Stage was developed using a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the Liver Cancer Study Group of Japan stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making. Background: Non-invasive biomarkers detected preoperatively are still inadequate for treatment decision making for patients with intrahepatic cholangiocarcinoma (ICC). In this study, we analyzed preoperative findings to establish a novel preoperative staging system (PRE-Stage) for patients with ICC. Methods: The clinical data of 227 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals were analyzed. Results: Cox proportional hazards regression analysis of survival revealed that a CRP–albumin–lymphocyte index < 3, central tumor location, and CA19-9 level > 40 U/mL were prognostic factors among the preoperatively obtained clinical findings (hazard ratios (HRs) of all three factors for disease-specific survival (DSS) and disease-free survival (DFS: 2.4–3.3 and 1.7–2.9; all p < 0.05). The PRE-Stage was developed using these three prognostic factors, and it was able to significantly predict DSS and DFS when the patients were stratified into four stages (p < 0.05). In addition, the PRE-Stage resulted in similar HRs as those of the Liver Cancer Study Group of Japan (LCSGJ) stage (HRs for DSS: PRE-Stage, 1.985; LCSGJ stage, 1.923; HRs for DFS: LCSGJ stage, 1.909, and PRE-Stage, 1.623, all p < 0.05). Conclusion: The PRE-Stage demonstrated similar accuracy in predicting the prognosis of ICC as that of the LCSGJ stage, which is based on postoperative findings. The PRE-Stage may contribute to appropriate treatment decision making. [ABSTRACT FROM AUTHOR]

Simple Summary: This review discusses multimodality treatment strategies for intrahepatic cholangiocarcinoma (iCC). Surgical resection remains the only potentially curative therapeutic option and the central cornerstone of treatment. Adjuvant systemic treatment will be recommended after resection or in the palliative setting. Increasing knowledge of phenotypic subclassification and molecular profiling allows investigation of targeted therapies as (neo-)adjuvant treatment. High-dose brachytherapy, internal radiation therapy, and transarterial chemoembolization are among the interventional treatment options being evaluated for unresectable iCC. Given the multiple options of multidisciplinary management, any treatment strategy should be discussed in a multidisciplinary tumor board and treatment should be directed by a specialized treatment center. Intrahepatic cholangiocarcinoma (iCC) is distinguished as an entity from perihilar and distal cholangiocarcinoma and gallbladder carcinoma. Recently, molecular profiling and histopathological features have allowed further classification. Due to the frequent delay in diagnosis, the prognosis for iCC remains poor despite major technical advances and multimodal therapeutic approaches. Liver resection represents the therapeutic backbone and only curative treatment option, with the functional residual capacity of the liver and oncologic radicality being deciding factors for postoperative and long-term oncological outcome. Furthermore, in selected cases and depending on national guidelines, liver transplantation may be a therapeutic option. Given the often advanced tumor stage at diagnosis or the potential for postoperative recurrence, locoregional therapies have become increasingly important. These strategies range from radiofrequency ablation to transarterial chemoembolization to selective internal radiation therapy and can be used in combination with liver resection. In addition, adjuvant and neoadjuvant chemotherapies as well as targeted therapies and immunotherapies based on molecular profiles can be applied. This review discusses multimodal treatment strategies for iCC and their differential use. [ABSTRACT FROM AUTHOR]