Ultrasomics in liver cancer: Developing a radiomics model for differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma using contrast-enhanced ultrasound.

BACKGROUND: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) represent the predominant histological types of primary liver cancer, comprising over 99% of cases. Given their differing biological behaviors, prognoses, and treatment strategies, accurately differentiating between HCC and ICC is crucial for effective clinical management. Radiomics, an emerging image processing technology, can automatically extract various quantitative image features that may elude the human eye. Reports on the application of ultrasound (US)-based radiomics methods in distinguishing HCC from ICC are limited. AIM: To develop and validate an ultrasomics model to accurately differentiate between HCC and ICC. METHODS: In our retrospective study, we included a total of 280 patients who were diagnosed with ICC (n = 140) and HCC (n = 140) between 1999 and 2019. These patients were divided into training (n = 224) and testing (n = 56) groups for analysis. US images and relevant clinical characteristics were collected. We utilized the XGBoost method to extract and select radiomics features and further employed a random forest algorithm to establish ultrasomics models. We compared the diagnostic performances of these ultrasomics models with that of radiologists. RESULTS: Four distinct ultrasomics models were constructed, with the number of selected features varying between models: 13 features for the US model; 15 for the contrast-enhanced ultrasound (CEUS) model; 13 for the combined US + CEUS model; and 21 for the US + CEUS + clinical data model. The US + CEUS + clinical data model yielded the highest area under the receiver operating characteristic curve (AUC) among all models, achieving an AUC of 0.973 in the validation cohort and 0.971 in the test cohort. This performance exceeded even the most experienced radiologist (AUC = 0.964). The AUC for the US + CEUS model (training cohort AUC = 0.964, test cohort AUC = 0.955) was significantly higher than that of the US model alone (training cohort AUC = 0.822, test cohort AUC = 0.816). This finding underscored the significant benefit of incorporating CEUS information in accurately distinguishing ICC from HCC. CONCLUSION: We developed a radiomics diagnostic model based on CEUS images capable of quickly distinguishing HCC from ICC, which outperformed experienced radiologists.

"Hepatic hilum area priority, liver posterior first": An optimized strategy in laparoscopic resection for type III-IV hilar cholangiocarcinoma.

BACKGROUND: In recent years, pure laparoscopic radical surgery for Bismuth-Corlette type III and IV hilar cholangiocarcinoma (HCCA) has been preliminarily explored and applied, but the surgical strategy and safety are still worthy of further improvement and attention. AIM: To summarize and share the application experience of the emerging strategy of "hepatic hilum area dissection priority, liver posterior separation first" in pure laparoscopic radical resection for patients with HCCA of Bismuth-Corlette types III and IV. METHODS: The clinical data and surgical videos of 6 patients with HCCA of Bismuth-Corlette types III and IV who underwent pure laparoscopic radical resection in our department from December 2021 to December 2023 were retrospectively analyzed. RESULTS: Among the 6 patients, 4 were males and 2 were females. The average age was 62.2 ± 11.0 years, and the median body mass index was 20.7 (19.2-24.1) kg/m2. The preoperative median total bilirubin was 57.7 (16.0-155.7) µmol/L. One patient had Bismuth-Corlette type IIIa, 4 patients had Bismuth-Corlette type IIIb, and 1 patient had Bismuth-Corlette type IV. All patients successfully underwent pure laparoscopic radical resection following the strategy of "hepatic hilum area dissection priority, liver posterior separation first". The operation time was 358.3 ± 85.0 minutes, and the intraoperative blood loss volume was 195.0 ± 108.4 mL. None of the patients received blood transfusions during the perioperative period. The median length of stay was 8.3 (7.0-10.0) days. Mild bile leakage occurred in 2 patients, and all patients were discharged without serious surgery-related complications. CONCLUSION: The emerging strategy of "hepatic hilum area dissection priority, liver posterior separation first" is safe and feasible in pure laparoscopic radical surgery for patients with HCCA of Bismuth-Corlette types III and IV. This strategy is helpful for promoting the modularization and process of pure laparoscopic radical surgery for complicated HCCA, shortens the learning curve, and is worthy of further clinical application.

Transposon-based oncogene integration in Abcb4(Mdr2)-/- mice recapitulates high susceptibility to cholangiocarcinoma in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC), difficult to diagnose and associated with high mortality. Lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis hinders development of novel treatments. Here we sought to develop such PSC-associated CCA model in mice. METHODS: Ten-week-old Mdr2-/- mice with congenital PSC-like disease, and healthy wild-type littermates were subjected to either modified retrograde biliary instillation or hydrodynamic tail vein injection of sleeping beauty transposon-transposase plasmid system with activated AKT (myr-AKT) and Yap (YapS127A) protooncogenes (SB AKT/YAP1). The role of TGFß was interrogated via ALK5 inhibitor (SB-525334) administration. Tumor phenotype, burden and desmoplastic reaction were analyzed histologically and via RNA-seq. RESULTS: While SB AKT/YAP1 plasmids via retrograde biliary injection caused tumors in Mdr2-/-, only 26.67% (4/15) of these tumors were CCA. Alternatively, hydrodynamic tail vein injection of SB AKT/YAP1 resulted in robust tumorigenesis in all fibrotic Mdr2-/- mice with high CCA burden compared to healthy mice. Tumors phenotypically resembled human CCA, expressed multiple CCA (but not hepatocellular carcinoma) markers, and exhibited a profound desmoplastic reaction. RNA-seq analysis revealed profound transcriptional changes in CCA evolving in PSC-like context, with specific alterations in multiple immune pathways. Pharmacological TGFß inhibition led to enhanced immune cell tumor infiltration, reduced tumor burden and suppressed desmoplastic collagen accumulation compared to placebo CONCLUSION: We established a new high-fidelity cholangiocarcinoma model in mice, termed SB CCA.Mdr2-/-, which recapitulates the increased susceptibility to CCA in the setting of biliary injury and fibrosis observed in PSC. Through transcriptomics and pharmacological studies, we show dysregulation of multiple immune pathways and TGFß signaling as potential drivers of CCA in PSC-like microenvironment. IMPACT AND IMPLICATIONS: There is a lack of animal models for primary sclerosing cholangitis (PSC) related cholangiocarcinoma (PSC-CCA). We have developed and characterized a new mouse model of PSC-CCA, termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. Global gene expression alterations were identified and standardized tools, including automated whole slide image analysis methodology for tumor burden and feature analysis, were established to enable systematic research into PSC-CCA biology and formal pre-clinical drug testing.

Machine learning based on biological context facilitates the identification of microvascular invasion in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a rare disease associated with a poor prognosis, primarily due to early recurrence and metastasis. An important feature of this condition is microvascular invasion (MVI). However, current predictive models based on imaging have limited efficacy in this regard. This study employed a random forest model to construct a predictive model for MVI identification and uncover its biological basis. Single-cell transcriptome sequencing, whole exome sequencing, and proteome sequencing were performed. The area under the curve of the prediction model in the validation set was 0.93. Further analysis indicated that MVI-associated tumor cells exhibited functional changes related to epithelial-mesenchymal transition and lipid metabolism due to alterations in the NF-kappa B and MAPK signaling pathways. Tumor cells were also differentially enriched for the IL-17 signaling pathway. There was less infiltration of SLC30A1+ CD8+ T cells expressing cytotoxic genes in MVI-associated ICC, whereas there was more infiltration of myeloid cells with attenuated expression of the MHC II pathway. Additionally, MVI-associated intercellular communication was closely related to the SPP1-CD44 and ANXA1-FPR1 pathways. These findings resulted in a brilliant predictive model and fresh insights into MVI.

Targeting Hippo/YAP in intrahepatic cholangiocarcinoma: Promising molecules in cancer therapy.

The tumorigenesis of intrahepatic cholangiocarcinoma (ICC) has been identified to be exceptionally involved in dysregulated Hippo/Yes-associated protein (YAP) signaling pathway (Hippo/YAP). Hippo/YAP functions as a master regulator engaged in a plethora of physiological and oncogenic processes as well. Therefore, the aberrant Hippo/YAP could serve as an Achilles' heel regarding the molecular therapeutic avenues for ICC patients. Herein, we comprehensively review the recent studies about the underlying mechanism of disrupted Hippo/YAP in ICC, how diagnostic values could be utilized upon the critical genes in this pathway, and what opportunities could be given upon this target pathway.

Quality of Life and Clinical Outcomes of Endosonography-Guided Biliary Drainage in Patients with Malignant Biliary Obstruction: A Single-Center, Prospective Analysis.

Introduction: Endosonography-guided biliary drainage (EUS-BD) serves as a rescue treatment modality for patients with malignant biliary obstruction when endoscopic retrograde cholangiopancreatography (ERCP) fails. Objectives: This study explores the effects of EUS-BD on liver function and quality of life (QoL). Patients and Methods: Patients with malignant biliary obstruction and failed ERCP were enrolled to undergo EUS-BD. QoL, including pruritus severity, was evaluated using EQ-5D-5L and PSS-10 questionnaires before and after EUS-BD. Serum bilirubin and liver function tests were measured on the procedure day, two days, and at least 14 days post-procedure. Results: During a 20-month study period, 1755 ERCPs were performed, with 595 for malignant cases. Of these, 49 underwent EUS-BD following failed ERCP, and 37 (54% women, age range 34-87 years) completed the 14-day follow-up. Pancreatic cancer was the most common (49%) condition, and the median hospital stay was 4 days. Serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased 2 and 14 days after EUS-BD (all p < 0.001). Pruritus significantly improved, with an average reduction of 5.19 points on the PSS-10 scale two weeks post-procedure (p < 0.001). EUS-BD led to improvements in anxiety and depression according to the EQ-5D-5L (p = 0.013). Conversely, deteriorations were observed in the Mobility, Self-Care, and Usual Activities domains over time (all p < 0.05). Successful EUS-BD enabled the resumption of chemotherapy in 11 (30%) patients. The median post-procedure survival was 112 (range 27-1030) days. Conclusions: EUS-BD improves liver parameters and some aspects of life quality in patients with malignant biliary obstruction, thereby increasing their eligibility for optimal palliative care.

Multiplexed immunohistochemical analysis of the immune microenvironment of biliary tract cancers pre- & post-neoadjuvant chemotherapy: case series.

Background: Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT. Case Description: Patients with BTC who underwent diagnostic biopsy, then NACT then resection between 2014-2018 were identified. Multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis was performed with a series of immune markers to characterize T-cells, immune checkpoints etc. on pre- & post-NACT tumor tissue. Density was calculated for each marker. The final analysis included five patients. Median age was 48 (range, 41-56) years, with 4 female, 4 intrahepatic cholangiocarcinoma and 1 gallbladder. All patients received gemcitabine/cisplatin as NACT (median of 5 cycles). Median time from diagnosis to surgery was 4.3 (range, 1.4-7.8) months. All patients were mismatch repair proficient (pMMR). NACT on average produced a depletion of all immune markers. Given small sample size, each patient was considered their own control and changes in mean cell densities post-NACT were calculated. Patient #2 with a 40-fold increase in PD-L1 expression & 5-fold decrease in CD8:FOXP3 ratio after NACT notably had the shortest disease-free interval (DFI). Patient #3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold with a decrease in PD-L1. Conclusions: Preliminary results suggest NACT may differentially modulate various compartments of the immune tumor contexture despite overall cell depletion. Future studies should focus on strategies to expand immune modulation of tumor microenvironment, including immune-oncology agents to augment the effects of chemotherapy.

CircUGP2 Suppresses Intrahepatic Cholangiocarcinoma Progression via p53 Signaling Through Interacting With PURB to Regulate ADGRB1 Transcription and Sponging miR-3191-5p.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients' prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co-activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR-3191-5p. As a result, ADGRB1 prevents MDM2-mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti-tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment.

Design of the distribution of iron oxide (Fe3O4) nano-particle drug in realistic cholangiocarcinoma model and the simulation of temperature increase during magnetic induction hyperthermia.

The prognosis for Cholangiocarcinoma (CCA) is unfavorable, necessitating the development of new therapeutic approach such as magnetic hyperthermia therapy (MHT) which is induced by magnetic nano-particle (MNPs) drug to bridge the treatment gap. Given the deep location of CCA within the abdominal cavity and proximity to vital organs, accurately predict the individualized treatment effects and safety brought by the distribution of MNPs in tumor will be crucial for the advancement of MHT in CCA. The Mimics software was used in this study to conduct three-dimensional reconstruction of abdominal computed tomography (CT) and magnetic reso-nance imaging images from clinical patients, resulting in the generation of a realistic digital geometric model representing the human biliary tract and its adjacent structures. Subsequently, The COMSOL Multiphysics software was utilized for modeling CCA and calculating the heat transfer law resulting from the multi-regional distribution of MNPs in CCA. The temperature within the central region of irregular CCA measured approximately 46°C, and most areas within the tumor displayed temperatures surpassing 41°C. The temperature of the inner edge of CCA is only 39 ∼ 41℃, however, it can be ameliorated by adjusting the local drug concentration through simulation system. For CCA with diverse morphologies and anatomical locations, the multi-regional distribution patterns of intratumoral MNPs and a slight overlap of drug distribution areas synergistically enhance intratumoral temperature while ensuring treatment safety. The present study highlights the practicality and imperative of incorporating personalized intratumoral MNPs distribution strategy into clinical practice for MHT, which can be achieved through the development of an integrated simulation system which incorporates medical image data and numerical calculations.

Delta-6 desaturase FADS2 is a tumor-promoting factor in cholangiocarcinoma.

Cholangiocarcinoma is a fatal disease with limited therapeutic options. We screened genes required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta-6 desaturase. FADS2 depletion reduced in vivo tumorigenicity and cell proliferation. In clinical samples, FADS2 was expressed in cancer cells but not in stromal cells. FADS2 inhibition also reduced the migration and sphere-forming ability of cells and increased apoptotic cell death and ferroptosis markers. Lipidome assay revealed that triglyceride and cholesterol ester levels were decreased in FADS2-knockdown cells. The oxygen consumption ratio was also decreased in FADS2-depleted cells. These data indicate that FADS2 depletion causes a reduction in lipid levels, resulting in decrease of energy production and attenuation of cancer cell malignancy.

Systematic profiling of mitochondria-related transcriptome in tumorigenesis, prognosis, and tumor immune microenvironment of intrahepatic cholangiocarcinoma: a multi-center cohort study.

Background: Mitochondrial dysfunction has been shown to play a critical role in cancer biology. However, its involvement in intrahepatic cholangiocarcinoma (iCCA) remains significantly understudied. Methods: RNA sequencing data of 30 pairs of iCCA and paracancerous tissues were collected from the First Affiliated Hospital of Wenzhou Medical University (WMU). The WMU cohort (n = 30) was integrated with public TCGA (n = 30) and GSE107943 (n = 30) datasets to establish a multi-center iCCA cohort. We merged the TCGA and GSE107943 cohorts into an exploration cohort to develop a mitochondria signature for prognosis assessment, and utilized the WMU cohort for external validation. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Hallmarker analyses were used for functional interpretation of iCCA associated mitochondria-related genes (MRGs). In addition, unsupervised clustering was performed to identify mitochondria-based iCCA subtypes with the data of three institutions. Further investigations were conducted to examine the impact of mitochondrial dysfunction on drug responses, alteration of the tumor immune microenvironment, and immune responses. Results: Two hundred and sixty-three iCCA-related MRGs were identified to be related to fatty acid metabolism, oxidative phosphorylation, and apoptosis. Through univariate and multivariate Cox, and LASSO analyses, a mitochondria signature with five optimal MRGs was established to evaluate the prognosis of iCCA patients with the AUC values ranged from 0.785 to 0.928 in the exploration cohort. The signature also exhibited satisfactory performance in the WMU cohort with AUC values of 0.817-0.871, and was identified as an independent risk predictor in both cohorts. Additionally, we found that patients with higher mitochondria score with poor prognosis presented lower infiltration levels of CD4+ T-cell, NK cells, and monocytes, and demonstrated higher sensitivity to targeted therapies, including sorafenib. Furthermore, two distant mitochondria-based subtypes were determined, and subtype 2 was associated with shorter survival time and immunosuppressive tumor microenvironment. Finally, the differential protein expression of five key MRGs was verified by Immunohistochemistry. Conclusion: We found mitochondrial dysfunction modulates aberrant metabolism, oxidative stress, immune responses, apoptosis, and drug sensitivity in iCCA. A mitochondria signature and two mitochondria-based iCCA subtypes were identified for clinical risk stratification and immunophenotyping.

[Synchronous primary multiple cancer: distal cholangiocarcinoma of the intrapancreatic common bile duct and intraductal papillary mucinous tumor associated with ductal adenocarcinoma of the pancreatic tail]. / Sinkhronnyi pervichno-mnozhestvennyi rak: distal'naya kholangiokartsinoma intrapankreaticheskoi chasti obshchego zhelchnogo protoka i vnutriprotokovaya papillyarnaya mutsinoznaya opukhol' v assotsiatsii s protokovoi adenokartsinomoi khvosta podzheludochnoi zhelezy.

We present a combination of distal cholangiocarcinoma of the intrapancreatic common bile duct and intraductal papillary mucinous tumor associated with ductal adenocarcinoma of the pancreatic tail. This clinical case is unique. When analyzing the literature, we found no any case of similar primary multiple malignant tumor. Importantly, final diagnosis of simultaneous malignant pancreatobiliary neoplasia is possible only via intraoperative biopsy after adequate morphological dissection and research of resected organ complex including molecular genetic analysis due to identical histological and immunohistochemical picture of ductal neoplasia.

Strategies for treating the cold tumors of cholangiocarcinoma: core concepts and future directions.

Cholangiocarcinoma (CCA) is a rare type of digestive tract cancer originating from the epithelial cells of the liver and biliary tract. Current treatment modalities for CCA, such as chemotherapy and radiation therapy, have demonstrated limited efficacy in enhancing survival rates. Despite the revolutionary potential of immunotherapy in cancer management, its application in CCA remains restricted due to the minimal infiltration of immune cells in these tumors, rendering them cold and unresponsive to immune checkpoint inhibitors (ICIs). Cancer cells within cold tumors deploy various mechanisms for evading immune attack, thus impeding clinical management. Recently, combination immunotherapy has become increasingly essential to comprehend the mechanisms underlying cold tumors to enhance a deficient antitumor immune response. Therefore, a thorough understanding of the knowledge on the combination immunotherapy of cold CCA is imperative to leverage the benefits of immunotherapy in treating patients. Moreover, gut microbiota plays an essential role in the immunotherapeutic responses in CCA. In this review, we summarize the current concepts of immunotherapy in CCA and clarify the intricate dynamics within the tumor immune microenvironment (TIME) of CCA. We also delve into the evasion mechanisms employed by CCA tumors against the anti-tumor immune responses. The context of combination immunotherapies in igniting cold tumors of CCA and the critical function of gut microbiota in prompting immune responses have also been annotated. Furthermore, we have proposed future directions in the realm of CCA immunotherapy, aiming to improve the clinical prognosis of CCA patients.

Incidence and Long-Term Outcomes of Biliary Tract Cancers in Olmsted County, Minnesota from 1976 to 2018.

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.

Targeting Isocitrate Dehydrogenase (IDH) in Solid Tumors: Current Evidence and Future Perspectives.

The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included.

Diagnostic performance of ultrasound elastography in differentiating hepatocellular carcinoma and intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

PURPOSE: To evaluate the diagnostic value of ultrasound elastography (USE) for characterizing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: The protocol was pre-registered a priori at ( https://osf.io/namvk/ ). Using PubMed, Web of Science, Embase, and Cochrane Library, we found studies up to April 20, 2024 by searching HCC, ICC, and USE as keywords. Parameters of USE were directly compared between HCC and ICC patients using random-effects bivariate model on STATA 17.0, MedCalc 20.0, and Psychometrica. Trim & fill method and sensitivity analysis were also performed. RESULTS: Eighteen studies were included with 1057 patients, consisting of 863 HCC lesions, 188 ICC lesions, and 6 mixed lesions. The pooled Emean values of HCC and ICC were 28.3 (CI = 19.8 to 36.8) and 44.0 (CI = 20.9 to 67.2). HCC tumors were 34.3% softer than ICC while peritumoral tissue in HCC lesions was 75% stiffer than ICC lesions based on Emean. The strain value index (tumoral-to-peritumoral ratio) in HCC patients was 49.4% less than that of ICC patients. USE demonstrated a pool sensitivity of 87% (CI = 73-95%), specificity of 82% (CI = 65-92%), positive likelihood ratio of 4.8 (CI = 2.2 to 10.3), negative likelihood ratio of 0.16 (CI = 0.07 to 0.37), and diagnostic odds ratio of 31 (CI = 7 to 127) in differentiation of ICC from HCC. CONCLUSION: By evaluating tumoral and pre-tumoral stiffness, along with strain value index, USE may provide a valuable quantitative diagnostic tool for accurately differentiating HCC and ICC.

Preoperative platelet count as an independent predictor of long-term outcomes among patients undergoing resection for intrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: An elevated platelet count may reflect neoplastic and inflammatory states, with cytokine-driven overproduction of platelets. The objective of this study was to evaluate the prognostic utility of high platelet count among patients undergoing curative-intent liver surgery for intrahepatic cholangiocarcinoma (ICC). METHODS: An international, multi-institutional cohort was used to identify patients undergoing curative-intent liver resection for ICC (2000-2020). A high platelet count was defined as platelets >300 *109/L. The relationship between preoperative platelet count, cancer-specific survival (CSS), and overall survival (OS) was examined. RESULTS: Among 825 patients undergoing curative-intent resection for ICC, 139 had a high platelet count, which correlated with multifocal disease, lymph nodes metastasis, poor to undifferentiated grade, and microvascular invasion. Patients with high platelet counts had worse 5-year (35.8% vs. 46.7%, p = 0.009) CSS and OS (24.8% vs. 39.8%, p < 0.001), relative to patients with a low platelet count. After controlling for relevant clinicopathologic factors, high platelet count remained an adverse independent predictor of CSS (HR = 1.46, 95% CI 1.02-2.09) and OS (HR = 1.59, 95% CI 1.14-2.22). CONCLUSIONS: High platelet count was associated with worse tumor characteristics and poor long-term CSS and OS. Platelet count represents a readily-available laboratory value that may preoperatively improve risk-stratification of patients undergoing curative-intent liver resection for ICC.

Hepatic arterial infusion of GEMOX plus systemic gemcitabine chemotherapy combined with lenvatinib and PD-1 inhibitor in large unresectable intrahepatic cholangiocarcinoma.

PURPOSE: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC). METHODS: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0. RESULTS: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs. CONCLUSIONS: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC.

Endoscopic Retrograde Cholangiopancreatography-Related Procedures for the Differential Diagnosis of Isolated Immunoglobin G4-Related Sclerosing Cholangitis and Perihilar Cholangiocarcinoma.

BACKGROUND/PURPOSE: Differential diagnosis of isolated immunoglobin (Ig)G4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma is challenging. We aimed to clarify the role of endoscopic retrograde cholangiography (ERCP)-related procedures in the differential diagnosis of isolated IgG4-SC and perihilar cholangiocarcinoma (PHCC). METHODS: Seven patients with hilar-type isolated IgG4-SC diagnosed at Hiroshima University Hospital and sixty-five patients with surgically resected invasive PHCC were enrolled, and the diagnostic yields of intraductal ultrasonography (IDUS), peroral cholangioscopy (POCS), and pathological examinations were determined. RESULTS: In six of seven (86%) patients with isolated IgG4-SC, the stricture was in the perihilar bile duct. IDUS showed that symmetrical wall thickening (40% vs. 5%, p = 0.04), homogeneous internal echo (80% vs. 5%, p < 0.001), and smooth outer margins (80% vs. 6%, p < 0.001) were more frequent in isolated IgG4-SC than in PHCC. POCS showed a smooth mucosal surface more frequent in isolated IgG4-SC (75% vs. 7%, p = 0.006). Only one patient had two pathological findings characteristic of IgG4-SC. The sensitivity for diagnosing PHCC was 81% using two or more combined sampling methods. CONCLUSIONS: Pathological examinations have limitations in the differential diagnosis of isolated-IgG4-SC and PHCC, and a diagnostic strategy that combines multiple ERCP-related procedures, including IDUS and POCS, is recommended.