Cases Of Intrahepatic Cholangiocarcinoma Research Articles

Misdiagnosis Based on Neoplastic Markers-Extremely High Alpha-Fetoprotein in Patients with Intrahepatic Cholangiocarcinoma with Literature Review of the Published Cases.

Background: Alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA 19-9) are two tumor markers that are widely used in the differential diagnosis in patients with primary liver tumors. Very high levels of AFP are sporadically observed in patients with intrahepatic cholangiocarcinoma (ICC) and may cause an incorrect initial diagnosis of hepatocellular carcinoma (HCC). Methods: Two cases of tumors in cirrhotic livers were described, in which the initial diagnosis, based on very high AFP levels (Patient I: 10,464 ng/mL, Patient II: 2212 ng/mL, reference range: ≤8.04 ng/mL) was HCC. In addition, the PubMed database was searched for cases of ICC with elevated AFP. Discussion: In both individuals, liver cirrhosis was diagnosed, but there was no typical rapid "washout" in the contrast-enhanced computed tomography. Based on the histological assessment of samples obtained in the core biopsies, the initially assumed diagnosis of HCC was changed to ICC in both cases. Only nine cases of patients with ICC and high AFP levels were found in the PubMed database. The AFP levels ranged from slightly elevated to over 16,000 ng/mL. Conclusions: A very high AFP level does not necessarily correlate with the presence of HCC. Therefore, the diagnosis has to be verified histologically, when the radiological imaging is uncertain in patients with liver cirrhosis.

Clinicopathologic and treatment characteristics of mixed hepatocellular carcinoma-intrahepatic cholangiocarcinoma (HCC-ICC).

e16218 Background: Mixed hepatocellular carcinoma-intrahepatic cholangiocarcinoma (HCC-ICC) represents a rare subtype of primary hepatic malignancy demonstrating morphological and biological features characteristic of both Hepatocellular Carcinoma (HCC) and Intrahepatic Cholangiocarcinoma (ICC). In this study, we describe the clinical and tumor characteristics of survival in HCC-ICC by using a large cohort. Methods: We selected patients diagnosed with HCC‐ICC, HCC, or ICC between 2011 and 2018 and were identified from the National Cancer Data Base (NCDB) using the International Classification of Diseases for Oncology codes. Baseline characteristics were delineated using percentages. Median overall survival (OS) was calculated using the Kaplan-Meier method. Demographic variables (age at diagnosis, gender, race, insurance status), comorbidity score, and treatment features were included. Short‐ and long‐term outcomes were evaluated through univariate analysis. Results: Out of 124,723 patients, 84.6% were diagnosed with HCC, 14.5% with ICC, and 1% with HCC‐ICC. Median survival was significantly better in HCC compared to HCC-ICC and ICC patients (16.2 months, 10.8 months, and 9.4 months, respectively, p < 0.001). Surgical intervention was used by 26.3% of HCC-ICC cases, 19.2% of ICC cases, and 9% of HCC cases. Multiagent chemotherapy was notably more utilized in ICC compared to HCC-ICC and HCC (42.6%, 22.8%, and 5.4%, respectively, p < 0.001). Meanwhile, single-agent chemotherapy was more commonly administered in HCC than in HCC-ICC and ICC (32.3%, 16.5%, and 11.4%, respectively, p < 0.001). Conclusions: HCC-ICC is an aggressive primary liver malignancy with a worse prognosis than HCC and ICC. The primary treatment approach for operable cases continues to be major hepatectomy combined with resection of hilar lymph nodes. Further research is urgently needed to better understand the exact role of the systemic therapies in managing HCC-ICC.

Expression of Fascin-1 and its diagnostic value in liver cancer

Although some studies have reported on the expression and clinical significance of Fascin-1 (FSCN1) in liver cancer, the clinical application and differential diagnosis value of FSCN1 in liver cancer are still unclear. The aim of this study was to analyze the expression level of FSCN1 protein in liver cancer tissues and explore its diagnostic and application value in differentiating between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The immunehistochemical analysis was used to detect the expression of FSCN1 in 108 cases of HCC, 26 cases of ICC, 23 cases of liver cirrhosis, and 11 cases of normal liver tissues. The differences in the positive expression rate and strong positive expression rate of FSCN1 among different groups were analyzed. The positive rate of FSCN1 in normal liver tissues, liver cirrhosis, HCC, and ICC tissues was 0.0% (0/11), 0.0% (0/23), 13.9% (15/108), and 92.3% (24/26), respectively, while the strong positive rate was 0.0% (0/11), 0.0% (0/23), 0.9% (1/108), and 69.2% (18/26), respectively. Both the positive rate and strong positive rate of FSCN1 in ICC tissues were significantly higher than those in HCC, liver cirrhosis, and normal liver tissues. Additionally, the positive rate of FSCN1 in moderately to poorly differentiated HCC tissues was 18.8% (15/80), significantly higher than in well-differentiated HCC (0.0%, 0/28) (P = 0.031). In liver cancer, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FSCN1 positive prediction for ICC were 92.3%, 86.1%, 61.5%, and 97.9%, respectively, whereas the sensitivity, specificity, PPV, and NPV of FSCN1 strong positive prediction for ICC were 69.2%, 99.1%, 94.7%, and 93.0%, respectively. These results suggest that FSCN1 may play an important role in the occurrence and progression of liver cancer, and it can be used as a novel diagnostic marker for ICC.

Prediction of prognosis of patients with radical resection of intrahepatic cholangiocarcinoma based on single cell omics

Objectives: To analyze the survival benefit of intrahepatic cholangiocarcinoma (ICC) radical resection based on single cell omics. Methods: This is a retrospective case-series study. ICC single-cell sequencing was integrated from four data sets in the Gene Expression Omnibus Database, with a total of 46 patients undergoing radical resection, to explore the characteristics of the microenvironment. Microarray data of 100 ICC cases was analyzed in the EMBI database with survival data. The infiltration abundance of each epithelial cell cluster was calculated in each microarray data sample using the ssGSEA algorithm. The key epithelial cell cluster associated with poor patient outcomes was explored. The clinical value of key marker genes in this subgroup was studied. Prognostic marker genes were selected using the univariate and multivariate Cox proportional hazards(CoxPH) model. The The CoxPH model was constructed by the target genes and a nomogram was drawn. Kaplan-Meier survival analysis was used to verify the relationship between score and prognosis of patients. The predictive power of the model was evaluated by receiver operating characteristic(ROC) curves, calibration curves, and decision curve analysis (DCA). Results: Epithelial cell clusters infiltrated almost exclusively in tumor tissue. The MT2A+ epithelial cell subset was associated with a poorer prognosis for patients with a high invasion abundance and patients characterized by infiltration of this group were defined as antioxidant. After screening marker genes in this cluster using a univariate and multivariate CoxPH model, the following genes were found to be independent prognostic factors: FILPIL, NFKBIA, PEG10, SERPINB5. The CoxPH model was constructed using the four gene expression levels, and the survival rate of patients in the high-risk group was significantly lower than those in the low-risk group (all P<0.05). The constructed nomogram had good discrimination and validity. The ROC curve showed that the predicted area under the curve was 0.779, 0.844 and 0.845 at 1, 3 and 5 years, respectively. Compared to clinical indicators, the model had better predictive power using the calibration curve and the DCA test. Conclusions: The MT2A+ epithelial cell group may be associated with the prognosis of patients with ICC, and the concept of ICC tissue typing of antioxidant and non-antioxidant types is proposed. The type of antioxidant may predict the poor prognosis of the patients, and postoperative adjuvant therapy and other means could be considered to improve the survival of the patients.

Abstract 4659: A genome-wide CRISPR screen identifies ARID1A as a potential resistance marker of IDH1 inhibitor in IDH1-mutant cholangiocarcinoma cell

Abstract Background: Isocitrate dehydrogenase 1 (IDH1) mutations have been identified in approximately 20% of intrahepatic cholangiocarcinoma cases. These predominant gain-of-function mutations at codon 132 lead to abnormal production of the oncometabolite D-2-hydroxyglutarate. Targeted pharmacological disruption of the IDH1 mutation demonstrates tumor growth inhibition in IDH1-mutated cholangiocarcinoma. However, the efficacy of an IDH1 inhibitor (AG-120) as monotherapy for IDH1-mutated cholangiocarcinoma has been proven clinically insufficient, suggesting a need for investigating predictive biomarkers. In this study, we employed a genome-wide CRISPR screen to pursue resistance mechanisms to pharmacological IDH1 inhibition. Methods: The screening utilized SNU1079 cells harboring the IDH1 R132C mutation and the Brunello genome-wide CRISPR knockout (KO) pooled library (Addgene #73178, Broad Institute GPP, 4 guides/gene). The read couns of sgRNAs were normalized to reads per million, and then log2 was transformed. The log fold change (LFC) of each sgRNA of the AG-120-treated group was determined relative to that of the DMSO-treated group. Hypergeometric distribution was used to determine statistical significance. P values per gene were calculated as the average -log10(P value) of individual sgRNAs. We validated the CRISPR screening outcomes in vitro using both IDH1R132C mutant (SNU1079) and IDH1R132S mutant (RBE) cells by WST-1 assays, clonogenic assay and competition assay. (Tsujino T et al. Nat Commun. 2023) In competition assay, GFP was constitutively expressed in ARID1A-knockout cells and cultured together with ARID1A intact cells, under treatment with 1 µM AG120 or DMSO for 21 days. Relative cell numbers of GFP-positive (ARID1A-KO) cells in comparison with GFP-negative (ARID1A intact) cells were quantified using a BD LSRFortessa Analyzer (BD Biosciences). Results: Based on a volcano plot analysis, we identified three genes (SMCHD1, ARID1A, and PGP) with LFC &amp;gt; 1.5. Following a recent report of frequent ARID1A alteration (20%; 84/412) in a clinical study (Boerner, et al. Hepatology. 2021), we focused our research on ARID1A (LFC = 1.531; −log10 P = 3.75). WST-1 assays and clonogenic assays as short-term (3-7 days) assays failed to validate the results of CRISPR screening; however, in competition assays under treatment with AG120, cells with ARID1A-KO exhibited significantly greater proliferation in comparison with ARID1A intact cells in two different cell lines (SNU1079, RBE). Conclusions: The results demonstrated that ARID1A disruption reduced the efficacy of the IDH1 inhibitor against IDH1-mutatedcholangiocarcinoma cells. Based on these findings, we are planning comprehensive analyses employing in vivo models and clinical data to substantiate these observations. Citation Format: Tomohiro Kondo, Osamu Kikuchi, Yafeng Wang, Yukie Nakai, Tomomi Ida, Yang Cao, Trang H. Vu, Yuki Kondo, Tomohiko Sunami, Yoshihiro Yamamoto, Tomoki Saito, Shigeki Kataoka, Atsushi Yamada, Masashi Kanai, Shinya Ohashi, Manabu Muto. A genome-wide CRISPR screen identifies ARID1A as a potential resistance marker of IDH1 inhibitor in IDH1-mutant cholangiocarcinoma cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4659.

Prognostic implications of tumor histology and microenvironment in surgically resected intrahepatic cholangiocarcinoma: a single institutional experience.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant neoplasm. Certain histologic features and the tumor microenvironment may impact disease progression. We aim to characterize the clinicopathologic features of ICC to identify prognostic factors. A total of 50 surgically resected ICC (partial or transplant) cases were analyzed. The cohort included 26 men and 24 women with a median age of 62years. Eighteen (36%) cases were multifocal ICC with a mean largest tumor size of 6.5cm. Neoadjuvant and adjuvant chemotherapy was done in eight (16%) and 33 (66%) patients, respectively. Histologically, 42 (84%) were small duct type, seven (14%) large duct type, and one mixed (2%). Thirty (60%) cases showed lymphovascular invasion (LVI) and 11 (22%) with perineural invasion (PNI). Twenty-eight (56%) cases demonstrated dense intratumoral hyaline fibrosis and 18 (36%) with tumor necrosis, each ≥ 10% tumor volume. On follow-up, 35 (70%) patients died of disease after a median disease-specific survival (DSS) of 21months. Univariate analysis revealed that hyaline fibrosis and adjuvant chemotherapy were associated with better DSS, while tumor size, multifocality, necrosis, and peritumoral neutrophil to lymphocyte ratio were associated with worse DSS. In contrast, age, sex, small vs. large duct types, LVI, and individual inflammatory cell counts were not significant prognostic factors. In summary, ICC is a heterogeneous malignancy with variable clinical courses associated with tumor burden, histology, and microenvironment. Targeting specific components within the tumor microenvironments may be a promising approach for treatment in the future.

The Incidences and Related CT Features of Vascular Lake Phenomenon on Angiography Before Chemoembolization.

To elucidate incidence rates of vascular lake phenomenon (VLP) in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatic metastasis (HMT) on transarterial angiography before chemoembolization, and to identity CT features predictive for it. A comprehensive evaluation involved 665 subjects for incidence analysis, comprising 527 of HCC, 33 of ICC and 105 of HMT. VLP was characterized as intratumoral contrast material pool persisting late into venous phase. Incidences were cataloged on both super-selective and common hepatic artery angiography. For CT features analysis, a subset of 182 cases were analyzed. Enhancement ratio served as an index for comparative analysis of nodule enhancement degrees. In HCC, incidence of VLP ascertained via super-selective angiography was 13.5%, whereas it as 7.8% on common hepatic artery angiography. Remarkably, no incidences of VLP were recorded in either ICC or HMT cases. On pre-interventional CT, the prevalence of pseudocapsule was statistically greater in VLP group than Non-VLP group (66.6% vs. 37.6%, P = 0.015). The Houndsfield units (HU) of tumors in plain scan (P = 0.007), arterial phase (P = 0.001), venous phase (P = 0.041), arterial phase enhancement ratio (P < 0.001) were statistically higher in VLP group compared to Non-VLP group. Arterial phase enhancement ratio (P = 0.025), presence of pseudocapsule (P = 0.001), HU of tumor in plain scan (P = 0.035) serve as independent risk factors for VLP manifestation. VLP is a distinct angiography phenomenon uniquely associated with HCC. High arterial phase enhancement ratio, presence of pseudocapsule, high HU of tumor in plain scan are independent risk factors for VLP.

Apparent diffusion coefficient in intrahepatic cholangiocarcinoma diffusion-weighted magnetic resonance imaging noninvasively predicts Ki-67 expression.

Tumor Ki-67 expression reflects prognosis and cancer grade, and biopsy-based preoperative assessment of Ki-67 expression is key to treatment. Apparent diffusion coefficient (ADC) values obtained with this imaging may noninvasively predict Ki-67 by reflecting tumor cell density and limited water molecule movement from irregular alignment. This study aimed to investigate the ability of ADC values to predict Ki-67 expression in intrahepatic cholangiocarcinoma (ICC). We retrospectively analyzed 39 cases of ICC confirmed by surgical pathology. All patients had undergone magnetic resonance imaging, and ADC values (mean, minimum, and maximum) were calculated. Ki-67 expression was assessed by immunohistochemistry, and patients were divided into groups of high (n=18) and low (n=21) Ki-67 expression. To assess the diagnostic performance of the ADC values for Ki-67 expression, we used the receiver operating characteristic curve and compared the areas under the curve (AUC). The mean and minimum ADC values were significantly lower in the group with high Ki-67 expression. For predicting high Ki-67 expression, the AUC values were 0.701 for mean ADC, 0.818 for minimum ADC, and 0.571 for maximum ADC. The diagnostic sensitivity and specificity of the minimum ADC values were 88.9% and 76.2%, respectively. In addition, with ADC values combined, the AUC increased to 0.831. Apparent diffusion coefficient is a useful predictor of Ki-67 expression level in ICC. Apparent diffusion coefficient values, especially minimum ADC values, can noninvasively predict ICC associated with high Ki-67 expression.

Use of Immunohistochemical Markers in Differentiation of Hepatocellular Carcinoma from Intrahepatic Cholangiocarcinoma and Metastatic Adenocarcinomatous Deposits in the Liver from Colon: A Cross-sectional Study

Introduction: Hepatocellular Carcinoma (HCC) is a major worldwide health problem due to its high incidence and mortality rates. The liver often becomes a site for metastasis from various primary locations, benefiting from its abundant blood supply. Distinguishing liver metastatic tumours from HCC can pose a diagnostic challenge, significantly impacting prognosis and treatment decisions. Aim: To differentiate between HCC, Intrahepatic Cholangiocarcinoma (ICC), and metastatic colonic adenocarcinoma in the liver using Hep par-1, Cytokeratin (CK) 7, CK19, and CK20 as immunohistochemical markers. The manual Tissue Microarray (TMA) technique was employed for present study. Materials and Methods: The present cross-sectional study was conducted in Department of Pathology at Government Stanley Medical College, Chennai, Tamil Nadu, India, spanning a three-year duration from July 2012 to June 2015. A total of 60 cases diagnosed histologically with HCC, ICC, and metastatic colonic adenocarcinoma in the liver were included. The manual TMA technique was used to create recipient blocks, and immunohistochemistry was performed to assess the expression of Hep par-1, CK7, CK19 and CK20. The sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predictive Values (NPV) of these markers in HCC, ICC, and metastatic colonic adenocarcinoma in the liver were analysed and tabulated using statistical software Statistical Package for Social Sciences (SPSS) version 16.0. Results: The study included a total of 60 cases, with 40 (66.7%) males and 20 (33.3%) females, ranging in age from 27 to 73 years with a mean age of 51.3 years. Among the cases, there were 30 (50%) cases of HCC, 14 (23%) cases of ICC, and 16 (27%) cases of metastatic colonic adenocarcinoma in the liver. The sensitivity, specificity, and PPV of Hep par-1 in distinguishing HCC from ICC and metastatic deposits were 80%, 100%, and 100%, respectively. The NPV of Hep par-1 in distinguishing HCC from ICC and metastatic deposits was 70% and 72%, respectively. The sensitivity, specificity, PPV, and NPV of CK7 in distinguishing ICC from HCC were 3.3%, 50%, 6.3%, and 34.1%, respectively. The sensitivity, specificity, PPV, and NPV of CK19 in distinguishing HCC from ICC and metastatic deposits were 0%, 50%, 0%, and 33.3%. The sensitivity, specificity, PPV, and NPV of CK20 in distinguishing HCC from ICC and metastatic deposits were 0%, 53.3%, 0%, and 34.8%, respectively. Conclusion: In conclusion, it was found that a panel of markers including Hep par-1, CK7, CK19 and CK20 can differentiate between HCC, ICC, and metastatic colonic adenocarcinoma in the liver. This differentiation is crucial for determining the appropriate treatment for patients by understanding the exact behaviour of the tumour.

Ultrasound findings of hepatic epithelioid hemangioendothelioma: comparison with other malignant hepatic tumors.

To investigate and compare the ultrasonic features of hepatic epithelioid hemangioendothelioma (HEHE) and other common hepatic malignancies, such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepatic metastatic tumor (HMT). A total of 37 patients with pathologically proven HEHE, 37 HCC cases, 37 ICC cases, and 37 HMT cases were enrolled from single hospital. The clinical characteristics and ultrasonic features of all cases were summarized and statistically analyzed. There were significant differences in sex and age between the HEHE group and other three groups (P < 0.001). The probability of HEHE infection with hepatitis B virus was lower than that of HCC and ICC groups (P < 0.05). The probability of elevated serum tumor markers in HEHE was significantly lower than that in the other three groups (P < 0.05). On conventional ultrasound (CUS), the probability of multiple lesions in HEHE was significantly higher than that in the other three groups (P < 0.05). On contrast-enhanced ultrasound (CEUS), the time to wash out in HEHE was significantly shorter than that of the other three groups (P < 0.001). The proportion of synchronous or slow enhancement in HEHE was significantly higher than that of the other three groups (P < 0.001). The proportion of HEHE with iso- or hypo-enhancement was significantly higher than in HCC and HMT groups (P < 0.05). HEHE mainly performed multiple hypoechoic lesions on CUS and displayed greater odds of synchronous enhancement in arterial phase, iso- or hypo-enhancement in peak time and wash out more quickly on CEUS, which allowed for differentiation from other common malignant tumors.

A Case of Intrahepatic Cholangiocarcinoma Diagnosed at the Same Site after 5 Years Who Treated for Liver Abscess

A Case of Intrahepatic Cholangiocarcinoma Diagnosed at the Same Site after 5 Years Who Treated for Liver Abscess

S2024 What a Fluke! A Case of Intrahepatic Cholangiocarcinoma in a Patient with Schistosoma Infection

S2024 What a Fluke! A Case of Intrahepatic Cholangiocarcinoma in a Patient with Schistosoma Infection

The significance of the predominant component in combined hepatocellular-cholangiocarcinoma: MRI manifestation and prognostic value.

To investigate the significance of the predominant component of combined hepatocellular-cholangiocarcinoma (cHCC-CC) in terms of MRI manifestation and its potential prognostic value compared to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A total of 300 patients with chronic liver disease from two centers were retrospectively enrolled, including 100 surgically proven cases of cHCC-CC, HCC, and ICC each. Univariate and multivariate regression analyses were performed to identify independent predictors for distinguishing HCC-predominant cHCC-CC and ICC-predominant cHCC-CC from HCC and ICC, respectively. Diagnostic models were constructed based on the independent features. Recurrence-free survival (RFS) was estimated and compared between groups. The predominant component was an independent predictor for RFS in cHCC-CC (hazard ratio = 1.957, P = 0.044). The presence of targetoid appearance (odds ratio(OR) = 10.907, P = 0.001), lack of enhancing capsule (OR = 0.072, P = 0.001) and arterial peritumoral enhancement (OR = 0.091, P = 0.003) were independent predictors suggestive of HCC-predominant cHCC-CC over HCC; their combination yielded an area under the curve of 0.756. No significant differences were observed in RFS between HCC-predominant cHCC-CC and HCC (P = 0.864). Male gender (OR = 4.049, P = 0.015), higher alpha fetoprotein (OR = 16.789, P < 0.001) and normal carbohydrate antigen 19-9 (OR = 0.343, P = 0.036) levels, presence of enhancing capsule (OR = 7.819, P < 0.001) and hemorrhage (OR = 23.526, P = 0.004), and lack of targetoid appearance (OR = 0.129, P = 0.005) and liver surface retraction (OR = 0.190, P = 0.021) were independent predictors suggestive of ICC-predominant cHCC-CC over ICC; their combination yielded an area under the curve value of 0.898. ICC-predominant cHCC-CC exhibited poorer survival with shorter RFS than ICC (P = 0.009). The predominant histopathological component is closely related to the imaging manifestation of cHCC-CC; and more importantly, it plays a significant prognostic role, which may alter the RFS prognosis of cHCC-CC.

Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis.

The aim of this study is to investigate certain genetic features of intrahepatic cholangiocarcinoma (ICCA). A total of 12 eligible ICCA patients were enrolled, and tumor tissues from the patients were subjected to next-generation sequencing of a multi-genes panel. Tumor mutation burden (TMB), mutated genes, copy number variants (CNVs), and pathway enrichment analysis were performed. The median TMB was 2.76 Mutation/Mb (range, 0-36.62 Mutation/Mb) in ICCA patients. The top two most commonly mutated genes in ICCA were KRAS (33%) and TP53 (25%). The co-mutations of KRAS and TP53 were 16.7% (2/12) in ICCA patients. Notably, patient P6 with the highest TMB did not have KRAS and TP53 mutations. Additionally, TP53 and/or KRAS alterations were significantly associated with poor progression-free survival than those with wild type (1.4 months vs 18 months). DNA damage repair and homologs recombinant repair deficiencies were significantly associated with high TMB in ICCA cases. In conclusion, we found that certain genetic mutations of TP53 and KRAS could predict poor prognosis in ICCA patients.

Efficacy and safety comparison of neoadjuvant chemotherapy followed by surgery and upfront surgery for treating intrahepatic cholangiocarcinoma: a systematic review and meta-analysis

Background and aimsCurrently, surgical resection is the most commonly performed and effective treatment for intrahepatic cholangiocarcinoma (ICC) worldwide. However, the prognosis of ICC is unsatisfactory. This study aimed to compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery and upfront surgery in treating intrahepatic cholangiocarcinoma (ICC). The study also intends to explore whether chemotherapy should be introduced before surgery and which populations should be considered for neoadjuvant chemotherapy.MethodFour databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, were searched from their inception dates to January 2022 for relevant articles. The statistical analysis was performed using the Review Manager Software (version5.3). The non-randomized interventions (ROBINS-I) was used to assess the methodological quality of included studies and the overall quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Moreover, the primary outcomes included 1-year, 3-year and 5-year overall survival (OS), while the secondary outcomes were R0 resection, 1-year, 3-year and 5-year recurrence-free survival (RFS), postoperative complications and ninety-day postoperative mortality.ResultsFive studies involving 2412 patients were included in this meta-analysis. There was no significant difference in 1-year OS, 3-year OS, 1-year, 3-year and 5-year RFS, postoperative complications and ninety-day postoperative mortality between the two groups. However, the meta-analysis showed that the neoadjuvant chemotherapy group had a better 5-year OS benefit in ICC patients than the upfront surgery group (OR = 1.27, 95% CI: 1.02–1.58), while the R0 resection rate was lower in neoadjuvant chemotherapy group than that in the upfront surgery group (OR = 0.49, 95% CI: 0.26–0.91).ConclusionCompared with the upfront surgery, neoadjuvant chemotherapy followed by surgery could prolong the 5-year OS without increasing the risk of postoperative complications in ICC patients. Considering that the patients in the neoadjuvant chemotherapy followed by surgery group had more advanced ICC cases, the benefits of neoadjuvant chemotherapy may be more significant in patients with more advanced ICC.

Abstract 101: Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma

Abstract Background &amp; Aim: Intrahepatic cholangiocarcinoma(ICC) accounts for about 5% of all primary liver cancer and is reported to be common in Southeast Asia and parts of Chile, but in recent years it has been increasing in other areas including Europe and the United States. ICC leads to a dismal outcome as the commonly used chemotherapy exhibit purely palliative effects on ICC, enabling only a limited improvement in survival until today. As ICC harbors few actionable target genes with inter-tumor genomic heterogeneity, ICC is considered to be one of the most intractable malignancies of all. Therefore, we implemented the multi-omics analysis especially with comprehension of the oncogenic metabolic changes to confer new treatment strategies. This study aims to unravel the evolution of ICC and identify ICC-specific metabolic pathways and essential targets for eradicating ICC. Approach: We collected 12 primary ICC cases and 77 specimens and conducted a multi-omics approach, including genomics, transcriptomics, proteomics, and metabolomics for each material. Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case indicates a “neutral evolution manner”, regardless of their tumor stage. Upregulation of BCAT1 and BCAT2 might enrich the ‘branched-chain amino acids (BCAA), such as Val, Leu, and Ile degradation pathway’. ICCs cases with the accumulated ubiquitous metabolites, BCAA exhibited poorer prognosis than those cases without BCAA accumulation significantly. Conclusions: Regardless of the inter-tumor heterogeneity in genomic aberrations among ICC cases, we discovered the ubiquitous enrichment of the BCAA metabolic pathway in each tumor. We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions. Citation Format: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 101.

Abstract 4667: Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma

Abstract Background: In recent years, patient tumor transplant models (PDX models) have attracted method that can predict the effects of anticancer drugs on patients. The PDX model is a technique in which the patient's tumor tissue is directly transplanted into immunodeficient mice. Tumors can grow three-dimensionally in a living mouse, so compared to culturing in petri dishes, the situation is like the growth of tumors in the patient's body. In addition, there are reports that the efficacy of anticancer drugs in patients and the results of administration of anticancer drugs in PDX show a high concordance rate, and it is attracting attention as a model that can predict efficacy in patients. In this time, we report on the establishment of cell lines using PDX mice for resected cases of intrahepatic cholangiocarcinoma in our hospital. Methods: Twelve patients who underwent surgical resection between September 2019 and December 2021 were included. After resected the tumor, the tumor was transplanted into up to 10 PDX mice, and cell lines were established from the formed tumor tissue. Results: Of the 12 cases, tumors formed in PDX mice after transplantation in 6 cases, and the median time to engraftment after the first transplantation was 133 days (75-188). Furthermore, among the 6 cases, 3 cases achieved the establishment of cell lines.Case1:moderately differentiated adenocarcinoma, tumor diameter 50mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th)Case2:well differentiated adenocarcinoma, tumor diameter 60mm, single, vascular invasion negative, no lymph node metastasis, Stage II (UICC 8th)Case 3:moderately differentiated adenocarcinoma, tumor diameter 55mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th) Conclusion: The cell line we established this time is a case of advanced cancer, and we would like to continue to increase the number of cases and continue to establish cell lines, which will lead to future research. Citation Format: Takashi Matsumoto. Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4667.

Intrahepatic cholangiocarcinoma with a liver abscess due to hepatic actinomycosis

BackgroundLiver tumors with liver abscesses are unusual and rarely reported. In particular, studies of intrahepatic cholangiocarcinoma with liver abscesses due to hepatic actinomycosis have not been reported.Case presentationA 73-year-old woman presented with swelling of the right hypochondrium. Computed tomography revealed a mass lesion that was continuous with the abdominal wall in the right lobe of the liver, suggesting a liver tumor invading the abdominal wall. A liver biopsy revealed intrahepatic cholangiocarcinoma with a liver abscess. The histopathological specimen contained bacterial masses of actinomycosis, and the cause of the liver abscess was determined to be hepatic actinomycosis. As a result of percutaneous drainage and antibiotic therapy, the part of the tumor attached to the abdominal wall disappeared; therefore, we assumed that most of the lesion was not cholangiocarcinoma but a liver abscess due to hepatic actinomycosis. Radical surgery for residual intrahepatic cholangiocarcinoma was performed after chemotherapy. Currently, the patient is alive without recurrence 2 years and 9 months after the operation.ConclusionWe encountered a difficult-to-diagnose case of intrahepatic cholangiocarcinoma with a liver abscess due to hepatic actinomycosis. A needle biopsy allowed early diagnosis and percutaneous drainage was an effective treatment.

A case of unresectable intrahepatic cholangiocarcinoma with a germline BRCA1 mutation.

Intrahepatic cholangiocarcinoma (ICC) is a malignant liver tumor with poor prognosis. Various mutations in cancer-predisposing genes have been reported in ICC, and germline BRCA1/2 mutations, which are the causative genes for hereditary breast and ovarian cancer syndrome (HBOC), have been reported in many patients with ICC. Here, we report a case of unresectable ICC with a germline BRCA1 mutation. A 73-year-old man was found to have a mass in the left lobe of the liver on abdominal ultrasonography during a medical check-up and was referred to our institution. Contrast-enhanced computed tomography revealed a 30-mm mass with a delayed enhancement pattern, tumor invasion into the major blood vessels, and enlarged regional lymph nodes. Ultrasound-guided percutaneous tumor biopsy revealed a well-differentiated adenocarcinoma, and the patient was diagnosed with clinical Stage IIIB ICC. Systemic chemotherapy with gemcitabine and cisplatin was initiated because of the unresectable nature of the disease. Regarding family history, his eldest daughter was diagnosed with HBOC with a germline BRCA1 mutation at the time of breast cancer surgery, and she developed pancreatic cancer seven years later. The patient underwent BRCA1 single-site analysis and was diagnosed with HBOC with a germline BRCA1 mutation.

Clinical utility of comprehensive genomic profiling in patients with unresectable primary liver cancer.

542 Background: Comprehensive genomic profiling (CGP) using tissue and blood specimens is covered by national health insurance for patients who have already received standard systemic therapy in Japan. We investigated the clinical utility of CGP in patients with unresectable primary liver cancer in real-world practice. Methods: We retrospectively investigated the clinical outcome of the patients with unresectable primary liver cancer. All patients received CGP between February 2021 and May 2022 at our institution. Results: 17 patients with unresectable primary liver cancer were included. 10 patients had hepatocellular carcinoma (HCC) and seven had intrahepatic cholangiocarcinoma (ICC). In HCC patients, the treatment line at CGP was 4th (n=5), 5th (n=4), and 6th-line (n=1). The samples were from liver tumor biopsy (n=2), surgical specimens of bone metastases (n=2), and blood (n=6). Clinically meaningful oncogene mutations were detected in all HCC cases. Seven of 10 patients were candidates for clinical trials, and 1 patient showed TMB-high. Six of the 7 patients could not participate in clinical trials due to renal dysfunction, low platelet counts, the immune-related adverse event of past therapy, or HBV infection. One patient with TMB high started pembrolizumab. In ICC patients, the treatment line at CGP was 1st (n=6), and 2nd -line (n=1). The samples were from liver tumor biopsy (n=5), blood (n=1) and surgical specimens of lung metastases (n=1). Clinically meaningful oncogene mutations were detected in all ICC cases. Six of 7 patients were candidates for clinical trials, and 1 patient showed MSI-high. One patient with MSI high started pembrolizumab, and one patient with FGFR2 fusion could use pemigatinib as 3rd line. The Overall survival duration of this patient with ICC (StageⅣB) was 26 months. In total, 13 of 17 patients were candidates for clinical trials, and 4 of 17 patients could receive personalized therapy according to the results of CGP. Conclusions: CGP in patients with unresectable primary liver cancer was useful in real-world practice. However, most patients could not participate in clinical trials because of adverse events associated with previous therapies. The best timing of CGP should be discussed in the future to provide more personalized therapies.