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Background: Biliary mucinous cystic neoplasms (BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center., Methods: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Affiliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021., Results: Among the 49 patients, 37 were female (75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients (44.9%) had no symptoms. Serum carbohydrate antigen (CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34 (70.8%) had low-grade intraepithelial neoplasms (LGINs), and 14 (29.2%) had high-grade intraepithelial neoplasms (HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin (CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival (OS) of BMCNs was not reached. The longest survival time was 137 months.The 5- and 10-year OS rates were 100% and 85.4%, respectively. The 5- and 10-year recurrence-free survival (RFS) rates were 93.9% and 80.2%, respectively., Conclusions: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Intrahepatic bile duct mucinous adenocarcinoma (IHBDMAC) is a rare pathological subtype of intrahepatic cholangiocarcinoma (IHCC), and its tumor biological features and survival outcomes have rarely been explored, especially when compared to the most common subtype, intrahepatic bile duct adenocarcinoma (IHBDAC). Therefore, the aim of this study was to explore the clinical features and survival outcomes of IHBDAC and IHBDMAC using the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2021. A total of 1,126 patients were included, with 1,083 diagnosed with IHBDAC and 43 diagnosed with IHBDMAC. Patients with IHBDMAC presented with a more advanced T stage (55.8% vs. 36.9%, P = 0.012) and higher rate of lymph node metastasis (37.2% vs. 24.9%, P = 0.070). Cox regression identified advanced T stage, lymph node metastasis, and distant metastasis as poor survival predictors, while chemotherapy and surgery were protective factors. Survival analyses revealed significantly worse overall survival (OS) and cancer-specific survival (CSS) for IHBDMAC compared to IHBDAC (P < 0.05). Even after matching, patients with IHBDMAC still had a worse prognosis than those with IHBDAC. These findings highlight the aggressive nature of IHBDMAC and the need for tailored therapeutic strategies. Future research should focus on prospective studies and molecular insights to develop targeted treatments for IHBDMAC.

Context.—: Intraductal papillary neoplasm of the bile duct (IPNB) is classified into types 1 and 2 based on criteria proposed in 2019. Recent studies investigated the clinicopathologic and molecular features of IPNB, which contributed to a more detailed understanding of this undercharacterized neoplasm., Objective.—: To summarize driver gene mutations, radiologic tumor evolution, and a potentially unique pattern of tumor progression in IPNB., Data Sources.—: Data were derived from a literature review and personal clinical and research experiences., Conclusions.—: In contrast to de novo cholangiocarcinoma, type 1 IPNB often has mutations in APC, CTNNB1, STK11, and GNAS. These molecular features are shared with intraductal papillary mucinous neoplasm of the pancreas; however, the frequencies of individual gene abnormalities differ between these 2 neoplasms. A radiologic review of sequential images suggested that type 1 IPNB is a slow-growing neoplasm, with an ∼1-cm increase in size every 2 to 3 years, and remains in a noninvasive state for many years. A similar papillary neoplasm may develop in the biliary tree years after the complete surgical resection of IPNB. The second neoplasm has the same genetic abnormalities as the first neoplasm, indicating intrabiliary implantation rather than multifocal lesions. In contrast to type 1 IPNB, most cases of type 2 IPNB have invasive malignancy at the initial presentation. Type 2 IPNB shares many clinicopathologic and molecular features with de novo cholangiocarcinoma, questioning the distinctness of this tumor entity. The molecular mechanisms underlying malignant transformation in IPNB warrant further study., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

A type of cholangiocarcinoma (CCA) characterized by peculiar histologic patterns and underlying adenofibromatous lesions has been reported in the literature mostly as individual case reports. This study aims to further clarify the defining characteristics of this spectrum of lesions. Clinicopathologic analysis of 8 biliary tumors with tubulocystic architecture arising in the background of adenofibroma-type lesions was performed. Three of these were also investigated with next-generation sequencing with a 174 genes panel. The patients were 5 males and 3 females, with a mean age of 64.6. All tumors were intrahepatic except for one perihilar that protruded into soft tissues. The mean size was 4.4 cm. At histology, all cases showed a peculiar and cytologically bland tubulocystic pattern that closely resembled tubulocystic-type kidney cancers, including back-to-back microcystic units that formed relatively demarcated nodules, and occurring in the background of adenofibromatous lesions. One case showed perineural invasion by otherwise deceptively benign-appearing microcystic structures, one had areas transitioning to intraductal tubulopapillary neoplasm, and 3 cases harbored more conventional small-duct CCA foci. In those 3 cases, both the tubulocystic and conventional CCA components were investigated by next-generation sequencing separately, and they shared the molecular alterations, including recurrent mutations in chromatin remodeling genes, such as ARID1A , BAP1 , and PBRM1 , and the actionable FGFR2-MCU fusion gene. In the limited follow-up, all but one were alive and free of disease after surgical resection. In conclusion, we described a distinct entity of CCA with specific histo-molecular features, for which we propose the designation of tubulocystic carcinoma of bile ducts., Competing Interests: Conflicts of Interest and Source of Funding: A.S.: consulting and speaker bureau from: MSD, Incyte, Medica s.r.l., NTP. C.L.: consulting and speaker bureau from: MSD, Medica s.r.l., NTP. For the remaining authors, none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The management of Bismuth-Corlette type IV hilar cholangiocarcinoma typically necessitates extensive hepatectomy, resection of the extrahepatic bile ducts, regional lymph node dissection, and reconstruction of the biliary tract; however, there is a high incidence of postoperative liver dysfunction and failure., Methods: A 64-year-old male patient was admitted to our department after 1 month of escalating jaundice and abdominal discomfort. Upon admission, his total bilirubin was 334 μmol/L and his direct bilirubin was 221 μmol/L. His carbohydrate antigen 19-9 was > 1200.00 U/mL, his carcinoembryonic antigen was 98.90 U/mL, and his α-fetoprotein was normal. Enhanced computed tomography (CT) and magnetic resonance imaging scans revealed a thickened and enlarged biliary tree extending from the common hepatic duct to the orifices of the left and right hepatic ducts., Results: The patient underwent total laparoscopic radical resection of S1 + S4, accompanied by radical lymphadenectomy with skeletonization and biliary reconstruction. The surgery was successfully conducted within 450 min, with a minimal blood loss of 200 mL. The histological grading was T2bN1M0 (stage III). CT on postoperative day 5 showed satisfactory postoperative recovery. The patient was discharged from the hospital on postoperative day 10 without complications, following which the patient underwent a regimen of single-agent capecitabine chemotherapy. Over a 20-month follow-up period, no recurrence was observed., Conclusions: Resection of hepatic segments S1 + S4 is a viable surgical option for hilar carcinoma in cases with poor liver function or when the carcinoma is confined to both hepatic ducts without invasion of the hepatic artery and portal vein., (© 2024. Society of Surgical Oncology.)

Background: Mass-forming intrahepatic cholangiocarcinoma (mICC) is the most frequent type of ICC. In contrast-enhanced computed tomography, mICC is visualized as a hypodense lesion with distal dilatation of intrahepatic bile ducts. The presented case illustrates the unusual manifestation of mICC in a 71-year-old male patient, where despite the extensive tumor mass and the hilar infiltration, the dilatation of intrahepatic bile ducts and cholestasis were not noted., Methods: A literature review on PubMed was performed. Primarily, 547 records were identified, and the titles and abstracts were systematically searched. Regarding the inclusion and exclusion criteria, 31 papers describing the non-cancerous liver lesions mimicking ICC were included in the further analysis., Results: In 41.9% of the analyzed non-cancerous lesions, the obstruction of the bile ducts was not noted, similar to our patient. A significant cholestasis has been found in 30.03% of analyzed patients. The invasion of the liver hilum was noted in one-third of the patients., Conclusions: Atypical radiological features in lesions suspected of ICC, such as the absence of intrahepatic bile-duct dilation, are common in benign lesions. In the case of radiologically atypical lesions suspected of ICC, the diagnostic imaging needs to be correlated with clinical data, and the diagnosis should be confirmed with a pathological examination.

Introduction: intrahepatic cholangiocarcinoma (ICCA) are rare, aggressive cancers that develop in second order or smaller bile ducts. The aim of this review is to systematically review the most important prognostic factors affecting the long-term outcomes of these patients. Material and Methods: articles conducted on this issue, written in English, published between from January 2000 to December 2023 in Cochrane Library, PubMed, Embase, MedLine, Web of Science, Elsevier, Google Scholar were systematically researched and reviewed. Results: ICCA are usually late diagnosed cancers because of the asymptomatic character, and curative procedures are often not feasible, only 20 to 30% of patients being fit for surgery. With the prognostic of this aggressive malignancy being baleful, the most important risk factors but also prognosis factors seem to be represented by socioeconomic factors, morphological presentation, dimensions, number and extension of the tumor as well as resection margins. Conclusions: once these factors are widely recognized and identified in each case, the clinician will be able to find the best treatment for these patients in order to improve the long-term outcomes., (Celsius.)

Background: This single-center retrospective study aimed to clarify the clinical and pathologic background of mass-forming intrahepatic cholangiocarcinomas., Methods: A total of 53 patients with mass-forming intrahepatic cholangiocarcinomas were selected from 2007 to 2021 and analyzed based on several parameters, including the preoperative computed tomography pattern (enhancement in the arterial phase of dynamic contrast-enhanced computed tomography), clinical data, and tumor microenvironment evaluated by immunohistochemistry. The hyperenhancement (n = 13) and hypoenhancement (n = 40) groups were defined using the 50% cutoff of tumors with higher attenuation than the liver parenchyma., Results: The hyperenhancement group was characterized by a better overall survival than the hypoenhancement group (5-year survival: 86% vs 27%, respectively; P < .001) and by a higher infiltration of peritumoral (92% vs 58%; P = .020) and intratumoral CD3-positive T lymphocytes (85% vs 35%; P = .002). Conversely, the hypoenhancement group was characterized by a higher infiltration versus peritumoral CD163-positive tumor-associated macrophages (60% vs 8%; P = .001), peritumoral pentraxin 3-positive tumor-associated macrophages (50% vs 15%; P = .024), and intratumoral α-smooth muscle actin-positive cancer-associated fibroblasts (15% vs 68%; P = .001). A multiple regression analysis was performed to predict overall survival from the microenvironment, and the independent poor predictor factors were low intratumoral CD3-positive T lymphocytes (hazard ratio = 2.75), high peritumoral (hazard ratio = 2.38), and intratumoral CD163-positive tumor-associated macrophages (hazard ratio = 2.81) (all P values < 0.05)., Conclusion: Compared with hypovascular, hypervascular mass-forming intrahepatic cholangiocarcinomas have better tumor immunity and prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

A 75-year-old man was referred to our department because of an enlarging intrahepatic mass detected on magnetic resonance imaging (MRI) follow-up for another disease. MRI showed hypointensity on T1-weighted imaging and hyperintensity on T2-weighted imaging in liver segment 4. Abdominal plain computed tomography (CT) indicated a low-density lesion with an unclear boundary, measuring approximately 4 cm × 3 cm in liver segment 4. Dynamic CT showed early rim enhancement and gradual central enhancement. Contrast-enhanced CT also showed occlusion of the portal vein in segment 4. As the possibility of intrahepatic cholangiocarcinoma could not be excluded on imaging studies, we performed laparoscopic left medial sectionectomy. Histologically, the lesion showed diminished numbers of hepatocytes with increased collagen fibers compared with normal, with no patent portal vein. We considered this lesion a reactive lesion caused by collapse of the liver parenchyma owing to localized obstruction and loss of the portal vein. This lesion was pathologically diagnosed as portal biliopathy. We experienced an extremely rare case of intrahepatic mass-forming portal biliopathy that mimicked a hepatic tumor, which was diagnosed by laparoscopic resection. Portal biliopathy rarely forms intrahepatic mass lesions and must be distinguished from a malignant hepatic tumor., (© 2024. Japanese Society of Gastroenterology.)

Follicular cholangitis (FC) is a rare non-neoplastic biliary tract disease first reported in 2003. A 74-year-old woman underwent extended left hepatectomy with a diagnosis of intrahepatic cholangiocarcinoma. Histopathological examination of the surgical specimen demonstrated no malignant findings, and lymphocytic infiltration with lymphoid follicles was observed within the bile duct wall. Along with immunohistochemical findings, the patient was diagnosed with FC. More than 3 years after surgery, the patient exhibited elevated hepatobiliary enzymes and total bilirubin. Endoscopic retrograde cholangiography revealed stricture and dilation from the extrahepatic bile duct to the right intrahepatic bile duct. Histopathological findings uncovered lymphocytic infiltration without malignant results. It was concluded that bile duct stricture due to FC had newly developed in her remnant liver. Subsequently, the patient developed hypoalbuminemia, and abdominal computed tomography revealed atrophy of the remnant liver and ascites accumulation. Esophagogastroduodenoscopy exposed the development of esophageal varices, which were not observed preoperatively. The patient was diagnosed with decompensated liver cirrhosis accompanied by portal hypertension. This case strongly suggests that long-term follow-up after surgery may be required for patients with FC for screening of potential new bile duct stricture and progression to liver cirrhosis due to cholestasis., (© 2024. Japanese Society of Gastroenterology.)

The peribiliary capillary plexus (PCP) regularly and densely lines the basal side of the lining epithelia of normal bile ducts. To determine the pathology of the PCP in high-grade biliary intraepithelial neoplasms (BilINs) and intraductal papillary neoplasms of the bile duct (IPNBs), a precursor of cholangiocarcinoma (CCA), and CCA. Seventy-six cases of surgically resected high-grade BilIN and 83 cases of IPNB were histopathologically examined using endothelial immunostaining of PCP; all cases of high-grade BilIN and 40 cases of IPNB were associated with invasive CCA. Invasive and preinvasive neoplasms were pathologically examined referring to a two-layer pattern composed of biliary lining epithelia and underlying PCP unique to the bile duct. All high-grade BilIIN cases had an underlying single layer of capillaries, similar to PCP (PCP-like capillaries). In 43% of the 83 cases of IPNB, these capillaries were regularly distributed in almost all stalks and intervening stroma of intraluminal neoplastic components, while in the remaining 57% of IPNB, capillaries were sparsely or irregularly distributed in intraluminal components showing cribriform or solid growth patterns composed of striking atypical neoplastic epithelia. Invasive carcinomas associated with high-grade BilIN and IPNB were not lined with capillaries. The loss of PCP-like capillaries underlying high-grade BilIN and in stalks or stroma of IPNB may be involved in the malignant progression of these precursors. Immunostaining of PCP could be a new pathological tool for the evaluation of malignant progression and vascular supply in CCA and its precursors., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: This study aimed to characterize intraductal papillary neoplasm of the bile duct (IPNB) in patients undergoing initial and recurrent surgical resection and to evaluate the appropriateness of surgical treatment strategies., Patients and Methods: This study included 14 patients who underwent liver resection for intrahepatic IPNB. We assessed intraoperative and postoperative clinicopathological factors in patients undergoing both initial and recurrent surgeries., Results: Four patients experienced recurrence after initial surgery; all underwent pancreaticoduodenectomy. Postoperative complications were classified as Clavien-Dindo Grade 1-2 in three patients and Grade IIIb in one patient. There were no in-hospital deaths., Conclusion: Pancreaticoduodenectomy for recurrent cases following hepatectomy for IPNB is considered safe within an acceptable range and contributes to a favorable long-term prognosis., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Competing Interests: H. Isayama was supported by research grants from Boston Scientific Japan and Fujifilm Corporation. The funding source had no role in the design, practice, or analysis of this study. K. Tomishima, A. Suzuki, K. Ito, S. Ishii, T. Fujisawa, and Y. Fukumura declare that they have no conflict of interest.

Cholangiocarcinoma (CCA) is a malignant tumor originating in the bile duct and its branching epithelium. Due to its high heterogeneity, there are no specific clinical indications at the early stage, the diagnosis is often in advanced CCA. With surgical resection, the 5-year postoperative survival rate (long-term survival rate) is very poor. The regimen of gemcitabine combined with platinum has been used as the first-line chemotherapy for advanced patients. In recent years, targeted therapy for a variety of malignant tumors has made great progress, showing good efficacy and safety in advanced CCA. However, the current targeted therapy of CCA still has many challenges, such as adverse reactions, drug resistance, and individual differences. Therefore, the researches need to further explore the targeted therapy mechanism of CCA malignancies in depth, develop more effective and safe drugs, and accurately formulate plans based on patient characteristics to further improve patient prognosis in the future. This article reviews the recent progress of targeted therapy for CCA, aiming to provide a strategy for the research and clinical work of targeted therapy for CCA.

Context: Cholangiocarcinoma with highly heterogeneous, aggressive, and multidrug resistance has a poor prognosis. Although babaodan (BBD) combined with cisplatin improved non-small cell lung cancer efficacy, its impact on overcoming resistance in cholangiocarcinoma remains unexplored., Objective: This study explored the role and mechanism of BBD on cisplatin resistance in cholangiocarcinoma cells (CCAs)., Materials and Methods: Cisplatin-resistant CCAs were exposed to varying concentrations of cisplatin (25-400 μg/mL) or BBD (0.25-1.00 mg/mL) for 48 h. IC 50 values, inhibition ratios, apoptosis levels, DNA damage, glutathione (GSH) levels, oxidized forms of GSH, total GSH content, and glutaminase relative activity were evaluated using the cell counting kit 8, flow cytometry, comet assay, and relevant assay kits., Results: BBD-reduced the cisplatin IC 50 in CCAs from 118.8 to 61.83 μg/mL, leading to increased inhibition rate, apoptosis, and DNA damage, and decreased expression of B-cell lymphoma-2, p-Yes-associated protein 1/Yes-associated protein 1, solute carrier family 1 member 5, activating transcription factor 4, and ERCC excision repair 1 in a dose-dependent manner with maximum reductions of 78.97%, 51.98%, 54.03%, 56.59%, and 63.22%, respectively; bcl2-associated X and gamma histone levels were increased by 0.43-115.77% and 22.15-53.39%. The impact of YAP1 knockdown on cisplatin-resistant CCAs resembled BBD. GSH, oxidized GSH species, total GSH content, and glutaminase activity in cisplatin-resistant CCAs with BBD treatment also decreased, while YAP1 overexpression countered BBD's effects., Discussion and Conclusion: This study provides a scientific basis for BBD clinical application and provides a new direction for BBD biological mechanism research.

Background: In primary sclerosing cholangitis (PSC), it is important to understand the cholangiographic findings suggestive of malignancy, but it is difficult to determine whether cholangiocarcinoma is present due to modifications caused by inflammation. This study aimed to clarify the appropriate method of pathological specimen collection during endoscopic retrograde cholangiopancreatography for surveillance of PSC., Methods: A retrospective observational study was performed on 59 patients with PSC. The endpoints were diagnostic performance for benign or malignant on bile cytology and transpapillary bile duct biopsy, cholangiographic findings of biopsied bile ducts, diameters of the strictures and upstream bile ducts, and their differences., Results: The sensitivity (77.8% vs. 14.3%, P = 0.04), specificity (97.8% vs. 83.0%, P = 0.04), and accuracy (94.5% vs. 74.1%, P = 0.007) were all significantly greater for bile duct biopsy than for bile cytology. All patients with cholangiocarcinoma with bile duct stricture presented with dominant stricture (DS). The diameter of the upstream bile ducts (7.1 (4.2-7.2) mm vs. 2.1 (1.2-4.1) mm, P < 0.001) and the diameter differences (6.6 (3.1-7) mm vs. 1.5 (0.2-3.6) mm, P < 0.001) were significantly greater in the cholangiocarcinoma group than in the noncholangiocarcinoma group with DS. For diameter differences, the optimal cutoff value for the diagnosis of benign or malignant was 5.1 mm (area under the curve = 0.972)., Conclusion: Transpapillary bile duct biopsy should be performed via localized DS with upstream dilation for the detection of cholangiocarcinoma in patients with PSC. Especially when the diameter differences are greater than 5 mm, the development of cholangiocarcinoma should be strongly suspected., (© 2024. Japanese Society of Gastroenterology.)

Intraductal papillary neoplasm of the bile duct (IPNB) is a heterogeneous disease similar to intraductal papillary mucinous neoplasm of the pancreas. These lesions have been recognized as one of the three major precancerous lesions in the biliary tract since 2010. In 2018, Japanese and Korean pathologists reached a consensus, classifying IPNBs into type l and type 2 IPNBs. IPNBs are more prevalent in male patients in East Asia and are closely related to diseases such as cholelithiasis and schistosomiasis. From a molecular genetic perspective, IPNBs exhibit early genetic variations, and different molecular pathways may be involved in the tumorigenesis of type 1 and type 2 IPNBs. The histological subtypes of IPNBs include gastric, intestinal, pancreaticobiliary, or oncocytic subtypes, but type 1 IPNBs typically exhibit more regular and well-organized histological features than type 2 IPNBs and are more commonly found in the intrahepatic bile ducts with abundant mucin. Due to the rarity of these lesions and the absence of specific clinical and laboratory features, imaging is crucial for the preoperative diagnosis of IPNB, with local bile duct dilation and growth along the bile ducts being the main imaging features. Surgical resection remains the optimal treatment for IPNBs, but negative bile duct margins and the removal of lymph nodes in the hepatic hilum significantly improve the postoperative survival rates for patients with IPNBs., (© 2024. Huazhong University of Science and Technology.)

Inversin-deficient (inv) mice have anomalies in liver and pancreatic development in addition to an inverted left-right axis of the body. The present study was undertaken to unveil mechanisms of bile and pancreatic duct development from immunohistochemical analyses of anomalies in inv mice. Intrahepatic bile ducts having proximodistal polarity in size and the height of their epithelia, and ductules were formed in livers of wild-type neonates. By contrast, in inv mice, ductal plates, precursor structures of intrahepatic bile ducts and ductules, persisted without the proximodistal polarity. Their epithelial cells did not acquire planar cell polarity (PCP) in terms of expression of tight junction proteins although they expressed bile duct markers, HNF1β and SOX9. They had an apicobasal polarity from expression of basal laminar components. Enlargement of the hepatic artery and poor connective tissue development, including the abnormal deposition of the extracellular matrices, were also noted in inv mice, suggesting that bile duct development was coupled to that of the hepatic artery and portal vein. In pancreata of inv neonates, neither the main pancreatic duct was formed, nor dilated duct-like structures had the morphological polarity from the connecting point with the common bile duct. Lumina of acini was dilated, and centroacinar cells changed their position in the acini to their neck region. Immunohistochemical analyses of tight junction proteins suggested that epithelial cells of the duct-like structures did not have a PCP. Thus, Invs may be required for the establishment of the PCP of the whole duct system in the liver and pancreas., (© 2023 American Association for Anatomy.)

Intrahepatic cholangiocarcinoma (iCCA) has been newly subclassified into two different subtypes: large-duct (LD) type and small-duct (SD) type. However, many cases are difficult to subclassify, and there is no consensus regarding subclassification criteria. LD type expresses the highly sensitive diagnostic marker S100 calcium-binding protein P (S100P), while SD type lacks sensitive markers. We identified osteopontin (OPN) as a highly sensitive marker for SD type. This study aimed to develop new subclassification criteria for LD-type and SD-type iCCA. We retrospectively investigated 74 patients with iCCA and subclassified them based on whole-section immunostaining of S100P and OPN. Of the 74 cases, 41 were subclassified as LD type, 32 as SD type, and one was indeterminate. Notably, all S100P-negative cases had OPN positivity. Seventy-three of the 74 cases (98.6%) were clearly and easily subclassified as LD or SD type using only these 2 markers. We also determined the value of immunohistochemistry in cases that were difficult to diagnose based on hematoxylin-eosin and Alcian blue-periodic acid-Schiff staining. Furthermore, we analyzed the clinicopathological characteristics and prognoses of these 2 subtypes. LD type was a poor prognostic factor on univariate analysis; it had significantly worse overall survival ( P = 0.007) and recurrence-free survival ( P < 0.001) than the SD type. In conclusion, we propose new subclassification criteria for iCCA based on immunostaining of S100P and OPN. These criteria may help pathologists to diagnose subtypes of iCCA, supporting future clinical trials and the development of medications for these 2 subtypes as distinct cancers., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis resistance in intrahepatic cholangiocarcinoma (ICC). Here we identified a group of stemness-related anoikis genes (SRAGs) via bioinformatic analysis of public data. Accordingly, a novel anoikis-related classification was established and it divided ICC into C1 and C2 type. Different type ICC displayed distinct prognosis, molecular as well immune characteristics. Furthermore, we found one key SRAGs via several machine learning algorithms. HK2 was up-regulated in tumor-repopulating cells (TRCs) of ICC, a kind of CSLCs with a potent resistance to anoikis. Its up-regulation may be caused by the activation of MTORC1 signaling in ICC-TRCs. And inhibition of HK2 significantly increased anoikis and decreased migration as well invasion in ICC-TRCs. Our studies provide an insight into the molecular mechanism underlying the resistance of ICC-TRCs to anoikis and enhance the evidences for targeting HK2 in ICC., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N-cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial-to-mesenchymal transition (EMT). However, we recently established N- and E-cadherin expression as hallmarks of normal hepatocytes and cholangiocytes, which are also preserved in HCC and iCCA. Therefore, we hypothesized that E- and/or N-cadherin may distinguish between carcinoma derived from the liver vs carcinoma of other origins. We comprehensively evaluated E- and N-cadherin in 3359 different tumors in a multicenter study using immunohistochemistry and compared our results with previously published 882 cases of PLC, including 570 HCC and 312 iCCA. Most carcinomas showed strong positivity for E-cadherin. Strong N-cadherin positivity was present in HCC and iCCA. However, except for clear cell renal cell carcinoma (23.6% of cases) and thyroid cancer (29.2%), N-cadherin was only in some instances faintly expressed in adenocarcinomas of the gastrointestinal tract (0%-0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0%-7.4%), breast (2.2%) as well as in urothelial (9.4%) and squamous cell carcinoma (0%-5.6%). As expected, N-cadherin was detected in neuroendocrine tumors (25%-75%), malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N-cadherin is a useful marker for the distinction of PLC vs liver metastases of extrahepatic carcinomas (P < .01)., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Cholangiocarcinoma (CCA) is a rare cancer of the bile duct epithelium, and in the last few decades its incidence rate has been increasing. It is associated with a high mortality rate due to late diagnosis and its aggressive nature. Many risk factors have been identified; some are more common in certain regions than others. CCA can be classified according to its anatomical location or macroscopic growth pattern, the latter being most helpful for imaging interpretation. Clinical features can vary from obstructive-like symptoms to nonspecific symptoms, such as weight loss and malaise. Imaging, specifically MRI/MRCP, is crucial in diagnosing CCA, staging, and treatment planning. Surgery with chemotherapy is the mainstay treatment option, and other palliative treatment options exist for those who have unresectable disease.

This study aimed to investigate the expression of protein regulator of cytokinesis 1 (PRC1) in cholangiocarcinoma (CHOL) and elucidate its potential impact as well as the underlying mechanisms governing the progression of CHOL. In this study, we used CHOL cells (HUCCT1, RBE, and CCLP1) and conducted a series of experiments, including qRT-PCR, cell counting kit-8 assays, EdU assays, flow cytometry, wound healing assays, Transwell assays, western blotting, double luciferase assays, and ELISA. Subsequently, a mouse model was established using cancer cell injections. Haematoxylin-eosin staining, along with Ki67 and TUNEL assays, were employed to assess tissue histopathology, cell proliferation, and apoptosis. Our findings revealed significantly elevated PRC1 expression in CHOL. According to bioinformatics analysis, it was found that the increased PRC1 level is correlated with the high tumour grades, metastases, and unfavourable prognoses. Notably, PRC1 knockdown inhibited cell viability, proliferation, migration, and invasion while promoting apoptosis in CHOL cells. Analysing TCGA-CHOL data and utilising transcription factor prediction tools (hTFtarget and HumanTFDB), we identified that genes positively correlated with PRC1 in TCGA-CHOL intersect with predicted transcription factors, revealing the activation of PRC1 by forkhead box protein M1 (FOXM1). Moreover, PRC1 was found to exert regulatory control over glycolysis and the mammalian target of rapamycin complex 1 (mTORC1) pathway in the context of CHOL based on KEGG and GSEA analysis. Collectively, these results underscore the pivotal role of PRC1 in CHOL progression, wherein it modulates glycolysis and the mTORC1 pathway under the regulatory influence of FOXM1., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: The application of three-dimensional (3D) reconstruction has been extensively adopted in hepatectomy navigation, 1 yet its utilization in laparoscopic radical resection of perihilar cholangiocarcinoma (pHCCA) remains underexplored., Video: A 54-year-old male patient, classified as Child-Pugh B, presented a small neoplasm situated at the left hepatic duct proximate to the right hepatic and common hepatic ducts. An enhanced abdominal computed tomographic scan identified a solitary lesion measuring 2.8 × 2.4 cm. 3D reconstruction exposed tumor invasion into the left hepatic artery and left portal vein. Given the lesion's unique location, a pure laparoscopic left hepatectomy and caudate lobectomy were executed using a no-touch en block technique post patient consent. Concurrently, extrahepatic bile duct resection, radical lymphadenectomy with skeletonization, and biliary reconstruction were performed., Results: The 3D reconstruction-guided laparoscopic left hepatectomy and caudate lobectomy were successfully completed in 425 min with minimal blood loss (50 mL). The histological grading was T2bN0M0 (stage II). The patient was discharged on the sixth postoperative day without complications, and postoperative treatment included mono-drug chemotherapy with capecitabine. No recurrence was observed at the 6-month follow-up., Conclusion: Our experience suggests that 3D reconstruction-guided laparoscopic radical resection may offer increased precision and efficiency in selected pHCCA patients. This approach can potentially yield outcomes comparable with or superior to open surgery, given standardized lymph node dissection by skeletonization, use of the no-touch en block technique, appropriate digestive tract reconstruction, and reduced bleeding and liver damage., (© 2024. Society of Surgical Oncology.)

Aims: The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD-iCCA) and large duct iCCA (LD-iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD- and LD-iCCA features in different tumour regions., Methods and Results: All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD- and LD-iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N-cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD- and LD-iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD- or LD-iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD- and LD-iCCA, seven patients (5.4%) of which had sufficient formalin-fixed, paraffin-embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD- and LD-iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD-iCCA but not in the LD-iCCA region of the tumour., Conclusions: A marked portion of patients with iCCA exhibits both SD- and LD-iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Introduction: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population., Methods: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m 2 , without need for bile duct or vascular resection were chosen as the benchmark group., Results: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0-67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days., Conclusions: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes., (© 2024. The Author(s).)

Introduction: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited., Methods: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases., Results: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients., Conclusions: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC., (© 2024. The Author(s).)

Background: Minimally invasive surgery for intrahepatic cholangiocarcinoma (ICC) remains challenging, especially in advanced patients., Patient and Method: A 66-year-old male was diagnosed with stage II ICC after a comprehensive evaluation and was scheduled for laparoscopic exploration and left hepatectomy., Results: The pure laparoscopic left hepatectomy was completed in 240 min, employing a no-touch en bloc technique and lymphadenectomy skeletonization. The patient was discharged 6 days after the operation without any complications and received gemcitabine and cisplatin treatment postoperatively. There was no recurrence during 14 months of follow-up., Conclusions: Our experience demonstrates that when utilizing the no-touch en bloc technique, standardized lymphadenectomy through skeletonization, and effective control of bleeding, surgeons with extensive expertise in laparoscopic hepatectomy can achieve results comparable to open surgery., (© 2024. Society of Surgical Oncology.)

Background: Perihilar cholangiocarcinoma is a challenging technique to be performed by minimally invasive approach being the type III among the most complex procedure. Nowadays, the robotic approach is gaining increasing interest among the surgical community, and more and more series describing robotic liver resection have been reported. However, few cases of minimally invasive Bismuth type IIIA cholangiocarcinoma have been reported. Robotic approach allows for a better dissection and suture thanks to the flexible and precise instruments movements, overcoming some of the limitations of the laparoscopic technique. Therefore, robotic technique can facilitate some of the critical steps of a technically demanding procedure, such as the extended right hepatectomy for perihilar cholangiocarcinoma Bismuth IIIA type., Methods: In this multimedia video we describe, for the first time in the literature, a full robotic surgical step-by-step technique with some tips and tricks for treating a perihilar cholangiocarcinoma Bismuth IIIA type, performing a radical extended right hemihepatectomy, including segment I combined with regional lymphadenectomy anf left bile duct reconstruction. A 55-year-old woman with obstructive jaundice (10 mg/dl) was referred to our center. The endobiliary brushing confirmed adenocarcinoma, and MRI/CT showed a focal perihilar lesion of 2 cm, including the main biliary duct bifurcation and extending up to the right duct (Bismuth Type IIIA hilar cholangiocarcinoma). After endoscopic biliary stents placement and 6 weeks after right portal vein embolization, the future liver remnant, including segments II and III, reached an enough hypertrophy volume with a ratio of 30%. A right hemihepatectomy with caudate lobe, including standard standard lymphadenectomy and left biliary duct reconstruction was performed., Results: The operation lasted 670 min with an estimated blood loss of 350 ml. Postoperative pathological examination revealed a moderately differentiated adenocarcinoma pT1N0 with 15 retrieved nodes and free margins. The patient experienced a type A biliary fistula and was discharged on the 21st postoperative day without abdominal drainage., Conclusions: Through the tips and tricks presented in this multimedia article, we show the advantages of the robotic approach for performing correctly one of the most complex surgeries. 1-7 ., (© 2024. The Author(s).)

Purpose: This study examined the impact of osteosarcopenia on recurrence and the prognosis after resection for extrahepatic biliary tract cancer (EBTC)., Methods: We retrospectively analyzed 138 patients after resection for perihilar cholangiocarcinoma (11), distal cholangiocarcinoma (54), gallbladder carcinoma (30), or ampullary carcinoma (43). Osteosarcopenia is defined as the concomitant occurrence of osteopenia and sarcopenia. We investigated the relationship between osteosarcopenia and the overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analyses., Results: Osteosarcopenia was identified in 38 patients (27.5%) before propensity score (PS) matching. In the multivariate analysis, the independent recurrence factors were the prognostic nutrition index (p = 0.015), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.004), perineural invasion (p = 0.002), and non-curability (p = 0.008), whereas the independent prognostic factors were prognostic nutrition index (p = 0.030), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.007), lymphatic invasion (p = 0.018), and non-curability (p = 0.004). After PS matching, there was no significant difference in the variables between the patients with and without osteosarcopenia (n = 34 each). The 5-year DFS and OS after PS matching in patients with osteosarcopenia were significantly worse than in patients without osteosarcopenia (17.6% vs. 38.8%, p = 0.013 and 20.6% vs. 57.4%, p = 0.0005, respectively)., Conclusions: Preoperative osteosarcopenia could predict the DFS and OS of patients after resection for EBTC., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

The aim of this study is to investigate the role of CFHR1 in bile duct carcinoma (BDC) and its mechanism of action, and we hope that our analysis and research will contribute to a better understanding of cholangiocarcinoma (BDC) disease genesis, progression and the development of new therapeutic strategies. The prognostic receiver operating characteristic curve of CFHR1 was generated using survival ROC. The ROC curve for CFHR1 showed that there is a correlation between CFHR1 expression and clinicopathological parameters and has an impact on poor prognosis. STRING was used to predict the protein-protein interaction network of the identified genes, and the Microenvironment Cell Populations counter algorithm was used to analyze immune cell infiltration within the BDC. The combined analysis showed that CFHR1 was found to be upregulated in BDC tissues, along with a total of 20 related differentially expressed genes (DEGs) (8 downregulated and 12 upregulated genes). Also, the results showed that the expression of CFHR1 is correlated with immune cell infiltration in tumor and immune cell markers in BDC (P < 0.05). In addition, we have verified experimentally the biological function of CFHR1. These findings suggest that CFHR1 may be a prognostic marker and a potential therapeutic target for BDC. Information regarding the detailed roles of CFHR1 in BDC could be valuable for improving the diagnosis and treatment of this rare cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

Background: The tumor microbiome has been characterized in several malignancies; however, no previous studies have investigated its role in intrahepatic cholangiocarcinoma (ICC). Hence, we explored the tumor microbiome and its association with prognosis in ICC., Methods: One hundred and twenty-one ICC tumor samples and 89 adjacent normal tissues were profiled by 16S rRNA sequencing. Microbial differences between tumor and adjacent nontumoral liver tissues were assessed. Tumor microbial composition was then evaluated to detect its association with prognosis. Finally, a risk score calculated by the tumor microbiota was accessed by the least absolute shrinkage and selector operator method (Lasso) to predict prognosis of ICC., Results: The tumor microbiome displayed a greater diversity than that in adjacent nontumoral liver tissues. Tumor samples were characterized by a higher abundance of Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteriota. Higher tumor microbial α diversity was associated with lymph node metastasis and predicted shortened overall survival (OS) and recurrence-free survival (RFS). A total of 11 bacteria were selected to generate the risk score by Lasso. This score showed potential in predicting OS, and was an independent risk factor for OS., Conclusion: In conclusion, our study characterized the tumor microbiome and revealed its role in predicting prognosis in ICC., (© 2024. Japanese Society of Gastroenterology.)

As two major types of primary liver cancers, the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have been well studied separately. However, a systemic assessment of the similarities and differences between the TIME of HCC and ICC is still lacking. In this study, we pictured a landscape of combined TIME of HCC and ICC by sequencing and integrating 41 single-cell RNA-seq samples from four different tissue types of both malignancies. We found that T cells in HCC tumors generally exhibit higher levels of immunosuppression and exhaustion than those in ICC tumors. Myeloid cells in HCC and ICC tumors also exhibit distinct phenotypes and may serve as a key factor driving the differences between their TIMEs. Besides, we identified a cluster of EGR1 + macrophages specifically enriched in HCC tumors. Together, our study provides new insights into cellular composition, states and interactions in the TIMEs of HCC and ICC, which could pave the way for the development of future therapeutic targets for liver cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Biliary intraepithelial neoplasia (BilIN), a noninvasive precursor of cholangiocarcinoma, can manifest malignant transformation. Since cholangiocarcinoma (CCA) may progress due to chronic inflammation in the bile ducts and gallbladder, choledochal cysts are considered a precursor to CCA. However, BilIN has rarely been reported in children, to date., Methods: We reviewed medical records of patients (< 18 years of age, n = 329) who underwent choledochal cyst excision at Asan Medical Center from 2008 to 2022. BilIN was diagnosed in 15 patients. Subsequent analyses were performed of the demographics, surgical procedures, clinical course, and outcomes in these patients. Subgroup analysis and multivariate logistic regression test were performed to identify factors influencing BilIN occurrence., Results: The mean age of the patients included in our study was 40.1 ± 47.6 months. In 15 patients, BilIN of various grades was diagnosed. Todani type I was prevalent in 80% of the patients. The median age at surgery was 17 months. During a mean follow-up of 63.3 ± 94.0 months, no adverse events such as stone formation in the remnant intrapancreatic common bile duct and intrahepatic duct or cholangiocarcinoma were observed, indicating a favorable outcome until now., Conclusions: The potential progression of choledochal cysts to BilIN in children was demonstrated. These results could underscore the importance of early and comprehensive excision of choledochal cysts, including resection margins for associated lesions and more thorough postoperative surveillance in patients with or at risk of BilIN., (© 2024. The Author(s).)

Purpose: Futibatinib, a covalently-binding inhibitor of fibroblast growth factor receptor (FGFR)1-4 gained approval for the treatment of refractory, advanced intrahepatic cholangiocarcinoma (iCCA) harboring an FGFR2 fusion/other rearrangement. An integrated analysis was performed to evaluate safety and provide guidance on the management of futibatinib-associated adverse events (AEs) in patients with unresectable/metastatic tumors, including iCCA., Patients and Methods: Data from three global phase I or II studies of futibatinib (NCT02052778; JapicCTI-142552) were pooled. AEs were graded per NCI CTCAE v4.03, where applicable. Safety was analyzed for patients receiving any futibatinib starting dose (overall population) and in those receiving the approved starting dose of 20 mg once every day., Results: In total, 469 patients with one of 33 known tumor types were analyzed, including 318 patients who received futibatinib 20 mg every day. AEs of clinical interest (AECI; any grade/grade ≥3) in the overall population included hyperphosphatemia (82%/19%), nail disorders (27%/1%), hepatic AEs (27%/11%), stomatitis (19%/3%), palmar-plantar erythrodysesthesia syndrome (PPES; 13%/3%), rash (9%/0%), retinal disorders (8%/0%), and cataract (4%/1%). Median time to onset of grade ≥3 AECIs ranged from 9 days (hyperphosphatemia) to 125 days (cataract). Grade ≥3 hyperphosphatemia, hepatic AEs, PPES, and nail disorders resolved to grade ≤2 within a median of 7, 7, 8, and 28 days, respectively. Discontinuations due to treatment-related AEs were rare (2%), and no treatment-related deaths occurred. AE management included phosphate-lowering medication and dose adjustments., Conclusions: Futibatinib showed a consistent and manageable safety profile across patients with various tumor types. AECIs were mostly reversible with appropriate clinical management., (©2024 The Authors; Published by the American Association for Cancer Research.)

Patients diagnosed with lymph node (LN) metastatic liver cancer face an exceedingly grim prognosis. In-depth analysis of LN metastatic patients' characteristics and tumor cells' interactions with human lymphatic endothelial cells (HLECs), can provide important biological and therapeutic insights. Here we identify at the single-cell level that S100A6 expression differs between primary tumor and their LN metastasis. Of particular significance, we uncovered the disparity in S100A6 expression between tumors and normal tissues is greater in intrahepatic cholangiocarcinoma (ICC) patients, frequently accompanied by LN metastases, than that in hepatocellular carcinoma (HCC), with rare occurrence of LN metastasis. Furthermore, in the infrequent instances of LN metastasis in HCC, heightened S100A6 expression was observed, suggesting a critical role of S100A6 in the process of LN metastasis. Subsequent experiments further uncovered that S100A6 secreted from tumor cells promotes lymphangiogenesis by upregulating the expression and secretion of vascular endothelial growth factor-D (VEGF-D) in HLECs through the RAGE/NF-kB/VEGF-D pathway while overexpression of S100A6 in tumor cells also augmented their migration and invasion. Taken together, these data reveal the dual effects of S100A6 in promoting LN metastasis in liver cancer, thus highlighting its potential as a promising therapeutic target., Competing Interests: Declaration of competing interest All authors have declared that no competing interest exists., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The term hepatolithiasis describes the presence of biliary stones within the intrahepatic bile ducts, above the hilar confluence of the hepatic ducts. The disease is more prevalent in Asia, mainly owing to socioeconomic and dietary factors, as well as the prevalence of biliary parasites. In the last century, owing to migration, its global incidence has increased. The main pathophysiological mechanisms involve cholangitis, bile infection and biliary strictures, creating a self-sustaining cycle that perpetuates the disease, frequently characterised by recurrent episodes of bacterial infection referred to as syndrome of "recurrent pyogenic cholangitis". Furthermore, long-standing hepatolithiasis is a known risk factor for development of intrahepatic cholangiocarcinoma. Various classifications have aimed at providing useful insight of clinically relevant aspects and guidance for treatment. The management of symptomatic patients and those with complications can be complex, and relies upon a multidisciplinary team of hepatologists, endoscopists, interventional radiologists and hepatobiliary surgeons, with the main goal being to offer relief from the clinical presentations and prevent the development of more serious complications. This comprehensive review provides insight on various aspects of hepatolithiasis, with a focus on epidemiology, new evidence on pathophysiology, most important clinical aspects, different classification systems and contemporary management., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interests for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Cholangiocarcinoma in patients with Choledochal cysts is rare in childhood; however, it seriously affects the prognosis of the disease. The key to addressing this situation lies in completely removing the extrahepatic cyst. We herein present a case report of a 3-year-old boy with cholangiocarcinoma associated with a choledochal cyst (CDC). Preoperative 3D simulation, based on CT data, played an important role in the treatment of this patient., (© 2024. The Author(s).)

Intrahepatic cholangiocarcinoma (ICC) is a high-grade malignant digestive system tumor with an insidious onset and unfavorable prognosis. Liensinine, a small molecule derived from plants, has been proven to have significant tumor suppressor activity in other cancers. However, there are no reports on whether liensinine can inhibit the proliferation or metastasis of ICC. This study aimed to explore the tumor-suppressive activity of liensinine in ICC and its underlying mechanisms. The phenotypic changes in ICC cells were monitored in vitro using cell function tests. Western blot and immunofluorescence analyses verified the efficacy of liensinine. Tumor-bearing nude mice were used to explore the effect of liensinine on tumors and its toxicity and side effects in vivo. Liensinine suppressed ICC cell proliferation and arrested the cell cycle at the G1 phase. The epithelial-mesenchymal transition (EMT) of ICC cells was also inhibited, thereby restraining their invasion and migration of tumor cells. In addition, this study found that the potential mechanism of liensinine inhibiting EMT may be via suppression of the TGF-β1/P-smad3 signaling pathway through hypoxia-inducible factor 1 alpha (HIF-1a). In vivo experiments showed that liensinine inhibited the growth of Hucc-T1 transplanted tumors in nude mice. Liensinine restrained the proliferation of ICC cells and suppressed EMT in ICC via the HIF-1a-mediated TGF-β1/P-smad3 signaling pathway., (© 2024 Wiley Periodicals LLC.)

Amino acid transporter LAT1 is highly upregulated in various cancer types, including cholangiocarcinoma (CHOL), and contributes to the rapid proliferation of cancer cells and disease progression. However, the molecular mechanisms underlying the pathological upregulation of LAT1 remain largely unknown. This study pursued the possibility of miRNA-mediated regulation of the LAT1 expression in CHOL cells. Using online target prediction methods, we extracted five candidate miRNAs commonly predicted to regulate the LAT1 expression. Three of them, miR-194-5p, miR-122-5p, and miR-126-3p, were significantly downregulated in CHOL cancer compared to normal tissues. Correlation analysis revealed weak-to-moderate negative correlations between the expression of these miRNAs and LAT1 mRNA in CHOL cancer tissues. We selected miR-194-5p and miR-122-5p for further analyses and found that both miRNAs functionally target 3'UTR of LAT1 mRNA by a luciferase-based reporter assay. Transfection of the miRNA mimics significantly suppressed the LAT1 expression at mRNA and protein levels and inhibited the proliferation of CHOL cells, with a trend of affecting intracellular amino acids and amino acid-related signaling pathways. This study indicates that the decreased expression of these LAT1-targeting tumor-suppressive miRNAs contributes to the upregulation of LAT1 and the proliferation of CHOL cells, highlighting their potential for developing novel cancer therapeutics and diagnostics., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was "substantial" (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was "slight" (κ-value, 0.201), while that of modified types 1 and 2 subclassification was "moderate" (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN., Competing Interests: Declaration of competing interest The authors have disclosed that they have no significant relationships with, or financial interest in any commercial companies pertaining to this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To explore the efficacy and safety of hepatic arterial infusion chemotherapy(HAIC) for unresectable hepatitis B-related intrahepatic cholangiocarcinoma(ICC). Methods: This is a retrospective controlled study. Data from 140 unresectable ICC patients who received HAIC treatment at Sun Yat-sen University Cancer Center from March 2015 to June 2023 were retrospectively collected, including 72 patients in the hepatitis B surface antigen(HBsAg)negative group (43 males and 29 females, aged (59.6±9.5)years(range: 34 to 81 years)), 68 cases in the HBsAg-positive group (48 males, 20 females, aged (53.4±11.4)years(range: 29 to 82 years)). HAIC treatment used the FOLFOX regimen combined with oxaliplatin, leucovorin,and fluorouracil. The differences in effects, prognosis,and adverse reactions between the two groups of patients after HAIC treatment were analyzed. All variables were expressed as categorical data. The χ 2 test or Fisher's exact probability method was used to compare between groups. The Kaplan-Meier method was used to draw survival curves. The difference of survival curve between groups were compared through the Log-rank test. Results: According to the Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1,the objective response rate(ORR) of the HBsAg-negative group was 23.2%(16/69),and the ORR of the HBsAg-positive group was 40.3%(25/62). The difference in ORR between the two groups was statistically significant( χ 2 =4.459, P =0.035). According to the modified RECIST(mRECIST) criteria,the ORR of the HBsAg-negative group was 27.5%(19/69), and the ORR of the HBsAg-positive group was 45.2%(28/62). The difference in ORR between the two groups was statistically significant( χ 2 =4.410, P =0.036). The median progression-free survival(PFS) of the HBsAg-negative group and the positive group were 7.1 months(95% CI : 5.8 to 13.2 months) and 7.3 months (95% CI : 5.7 to 10.3 months), respectively, and the median overall survival(OS) were 16.3 months (95% CI : 12.5 to 33.9 months) and 15.9 months (95% CI : 9.2 to 20.7 months) respectively. There were no statistically significant differences in PFS and OS between the two groups (both P >0.05). The main serious adverse reactions of the two groups of patients included increased AST, increased ALT, thrombocytopenia,and neutropenia. There were no statistically significant differences in various adverse reactions between the two groups after HAIC treatment (all P >0.05). Conclusion: Patients with HBsAg-positive unresectable ICC are more likely to benefit from HAIC treatment.