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On the basis of morphological features, we subclassified 189 intrahepatic cholangiocarcinomas into two subtypes: bile duct and cholangiolar. The cholangiolar type is composed of cuboidal to low columnar tumor cells that contain scanty cytoplasm. The bile duct type is composed of tall columnar tumor cells arranged in a large glandular pattern. In this study, 77 (41%) tumors were classified as the cholangiolar type and 112 (59%) tumors were classified as the bile duct type. The cholangiolar-type intrahepatic cholangiocarcinoma was more frequently associated with viral hepatitis, whereas all but one intrahepatic cholangiocarcinoma associated with intrahepatic lithiasis were classified as the bile duct type. Biliary intraepithelial neoplasm or intraductal papillary neoplasm of the bile duct could be identified in 50 bile duct-type intrahepatic cholangiocarcinomas (45%), but in only 3 cholangiolar-type intrahepatic cholangiocarcinomas (4%). Cholangiolar-type intrahepatic cholangiocarcinomas frequently expressed N-cadherin, whereas bile duct intrahepatic cholangiocarcinomas were more likely to express S100P, Trefoil factor 1, and anterior gradient 2. KRAS is mutated in 23 of 98 (23%) bile duct-type intrahepatic cholangiocarcinomas and in only 1 of 76 (1%) cholangiolar-type intrahepatic cholangiocarcinomas. Cholangiolar-type intrahepatic cholangiocarcinomas had a higher frequency of IDH1 or 2 mutations than did the bile duct-type intrahepatic cholangiocarcinomas. The molecular features of the bile duct-type intrahepatic cholangiocarcinoma were similar to those of hilar cholangiocarcinoma. Patients with the cholangiolar-type intrahepatic cholangiocarcinoma had higher 5-year survival rates than those of patients with the bile duct-type intrahepatic cholangiocarcinoma. Our results indicated that intrahepatic cholangiocarcinoma was a heterogeneous tumor. Subclassification of intrahepatic cholangiocarcinomas based on cholangiocytic differentiation divides them into two groups with different etiologies, clinical manifestations, and molecular pathogeneses.

Backgrounds Stent migration following endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) may sometimes be fatal because there are no adhesions between the biliary tract and stomach. To prevent stent migration and minimize the stent length in the abdominal cavity, we recently performed EUS-HGS using the technique of releasing the stent within the scope channel. Aims To examine the technical feasibility of the intra-scope channel stent release technique. Methods Forty-one consecutive patients who underwent EUS-HGS were enrolled. Between October 2015 and December 2015, EUS-HGS was performed using the extra-scope channel release technique, while the intra-scope channel release technique was performed between January 2016 and March 2016. Results The distance between the hepatic parenchyma and the stomach wall after EUS-HGS in the intra-scope channel stent release group was significantly shorter than that in the extra-scope channel release group (0.66 ± 1.25 vs 2.52 ± 0.97, P  < 0.05). Adverse events, such as biloma or stent migration, were seen in only the extra-scope channel release group. Conclusion In conclusion, although additional cases and randomized controlled studies using metal stents of various lengths are needed, our technique is likely to be clinically useful for the prevention of early and late stent migration.

Background The objective of the current study was to investigate both short- and long-term outcomes of patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) stratified by extent of hepatic resection relative to overall final pathological margin status. Methods One thousand twenty-three patients with ICC who underwent curative-intent resection were identified from a multi-institutional database. Demographic, clinicopathological, and operative data, as well as overall (OS) and recurrence-free survival (RFS) were compared among patients undergoing major and minor resection before and after propensity score matching. Results Overall, 608 (59.4%) patients underwent major hepatectomy, while 415 (40.6%) had a minor resection. Major hepatectomy was more frequently performed among patients who had large, multiple, and bilobar tumors. Roughly half of patients ( n  = 294, 48.4%) developed a postoperative complication following major hepatectomy versus only one fourth of patients ( n  = 113, 27.2%) after minor resection ( p  < 0.001). In the propensity model, patients who underwent major hepatectomy had an equivalent OS and RFS versus patients who had a minor hepatectomy (median OS, 38 vs. 37 months, p  = 0.556; and median RFS, 20 vs. 18 months, p  = 0.635). Patients undergoing major resection had comparable OS and RFS with wide surgical margin (≥10 and 5–9 mm), but improved RFS when surgical margin was narrow (1–4 mm) versus minor resection in the propensity model. In the Cox regression model, tumor characteristics and surgical margin were independently associated with long-term outcome. Conclusions Major hepatectomy for ICC was not associated with an overall survival benefit, yet was associated with increased perioperative morbidity. Margin width, rather than the extent of resection, affected long-term outcomes. Radical parenchymal-sparing resection should be advocated if a margin clearance of ≥5 mm can be achieved.

Background The present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status. Method Patients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status. Results Among 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2–8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin ( n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1–3 mm 38.5% vs. 3–10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1–3 mm 22.8% vs. 3–10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35–3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58–3.11, p = 0.50). Conclusion R0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology.

Intrahepatic cholangiocarcinomas were classified into two types based on their microscopic appearance. Tumors with histologic similarities to hilar cholangiocarcinomas (predominantly ductal adenocarcinomas with minor tubular components, if present, restricted to the invasive front) were defined as the perihilar type, whereas the others were classified as peripheral cholangiocarcinomas. Among the 47 cases examined in the present study, 26 (55%) were classified as the perihilar type, whereas 21 (45%) were the peripheral type. The perihilar type had higher pT stages and more frequently showed a periductal-infiltrating gross appearance and microscopic perineural infiltration than peripheral cholangiocarcinomas. The presence of low-grade biliary intraepithelial neoplasia in the adjacent bile ducts was only found in perihilar cholangiocarcinomas (6/21, 29%). The immunophenotype also differed between the two types with MUC5AC and MUC6 being more commonly expressed in the perihilar type. One-third of perihilar cholangiocarcinomas lacked the expression of SMAD4, suggesting SMAD4 mutations, whereas the loss of BAP1 expression and IDH1 mutations were almost restricted to the peripheral type (35 and 15%, respectively). Patients with perihilar cholangiocarcinoma had worse overall survival than those with peripheral cancer (P=0.027). A multivariate analysis identified the histologic classification as an independent prognostic factor (P=0.005, HR=3.638). Comparisons between intrahepatic and hilar cholangiocarcinomas also revealed that the molecular features and prognosis of perihilar cholangiocarcinomas were very similar to those of hilar cholangiocarcinomas. In conclusion, this histology-based classification scheme of intrahepatic cholangiocarcinomas will be useful and clinically relevant because it represents different underlying molecular features and has an independent prognostic value.

BackgroundEndoluminal radiofrequency ablation (RFA) has been promoted as palliative treatment for patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) in order to improve biliary drainage and eventually prolong survival. No high level evidence is, however, available on this technique.DesignIn this randomised controlled study, we compared endoluminal RFA plus stenting with stenting alone (control group) in patients with malignant biliary obstruction; metal stents were primarily placed. Primary outcome was overall survival; secondary outcomes were stent patency, quality of life and adverse events. In a superiority design, survival was assumed to be doubled by RFA as compared with 6.4 months in the control group (n=280).ResultsA total of 161 patients (male:female 90:71, mean age 71±9 years) were randomised before recruitment was terminated for futility after an interim analysis. Eighty-five patients had CCA (73 hilar, 12 distal) and 76 had pancreatic cancer. There was no difference in survival in both subgroups: for patients with CCA, median survival was 10.5 months (95% CI 6.7 to 18.3) in the RFA group vs 10.6 months (95% CI 9.0 to 24.8), p=0.58)) in the control group. In the subgroup with pancreatic cancer, median survival was 6.4 months (95% CI 4.3 to 9.7) for the RFA vs 7.7 months (95% CI 5.6 to 11.3), p=0.73) for the control group. No benefit was seen in the RFA group with regard to stent patency (at 12 months 40% vs 36% in CCA and 66% vs 65% in PDAC), and quality of life was unchanged by either treatment and comparable between the groups. Adverse events occurred in seven patients in each groups.ConclusionA combination of endoluminal RFA and stenting was not superior to stenting alone in prolonging survival or improving stent patency in patients with malignant biliary obstruction.Trial registration number NCT03166436.

PurposeThe aim of this retrospective study was to develop and validate a preoperative nomogram for predicting microvascular invasion (MVI) in patients with intrahepatic mass-forming cholangiocarcinoma (IMCC) based on magnetic resonance imaging (MRI). MethodsIn this retrospective study, 224 consecutive patients with clinicopathologically confirmed IMCC were enrolled. Patients whose data were collected from February 2010 to December 2020 were randomly divided into the training (131 patients) and internal validation (51 patients) datasets. The data from January 2021 to November 2021 (42 patients) were allocated to the time-independent validation dataset. Univariate and multivariate forward logistic regression analyses were used to identify preoperative MRI features that were significantly related to MVI, which were then used to develop the nomogram. We used the area under the receiver operating characteristic curve (AUC) and calibration curve to evaluate the performance of the nomogram. ResultsInterobserver agreement of MRI qualitative features was good to excellent, with κ values of 0.613–0.882. Multivariate analyses indicated that the following variables were independent predictors of MVI: multiple tumours (odds ratio [OR]) = 4.819, 95% confidence interval [CI] 1.562–14.864, P = 0.006), ill-defined margin (OR = 6.922, 95% CI 2.883–16.633, P < 0.001), and carbohydrate antigen 19–9 (CA 19–9) > 37 U/ml (OR = 2.890, 95% CI 1.211–6.897, P = 0.017). A nomogram incorporating these factors was established using well-fitted calibration curves. The nomogram showed good diagnostic efficacy for MVI, with AUC values of 0.838, 0.819, and 0.874 for the training, internal validation, and time-independent validation datasets, respectively.ConclusionA nomogram constructed using independent factors, namely the presence of multiple tumours, ill-defined margins, and CA 19–9 > 37 U/ml could predict the presence of MVI. This can facilitate personalised therapeutic strategy and clinical management in patients with IMCC.

Purpose This study aims to assess the long-term postoperative changes in the preoperative dilated intrahepatic bile duct (IHBD) in pediatric patients with congenital biliary dilatation (CBD). Methods The postoperative serial changes in the preoperative dilated left IHBD in pediatric patients who underwent appropriate excision surgery were evaluated using magnetic resonance cholangiopancreatography (MRCP). Results The IHBD dilation significantly decreased at a median of 1.5 years and was maintained up to 15 years postop in the 24 CBD patients, regardless of the methods of biliary reconstruction. In the 16 patients with apparent preoperative IHBD dilation (5 mm or more), a significant rapid decrease was also observed and maintained up to 15 years postop, regardless of age at surgery. However, a patient with failed rapid reduction at 1.5 years postop and sustained IHBD dilatation of more than 5 mm developed cholangitis 15 years postop with suspected residual congenital stenosis at the hepatic hilum. Conclusions Performing the appropriate excision surgery resulted in a rapid reduction of the preoperative IHBD dilation and maintained long-term reduced IHBD dilation. Patients with failed rapid reduction and sustained dilatation of the IHBD would have residual stenosis and should be carefully followed up for possible late cholangitis.

Intrahepatic bile duct (IHBD) development produces a morphologically heterogeneous network of large “ducts” and small “ductules” by adulthood. IHBD formation is closely linked to developmental specification of biliary epithelial cells (BECs) starting as early as E13.5, but mechanisms regulating differential IHBD morphology remain poorly understood. Here, we show that duct and ductule development has distinct genetic requirements, with Sox9 required to form the developmental precursors to peripheral ductules in adult livers. By optimizing large-volume IHBD imaging, we find that IHBDs emerge as a homogeneous webbed structure by E15.5 and undergo morphological maturation through 2 weeks of age. Developmental knockout of Sox9 leads to decreased postnatal branching morphogenesis, resulting in adult IHBDs with normal ducts but significantly fewer ductules. In the absence of Sox9 , BECs fail to mature and exhibit elevated TGF-β signaling and Activin A. Exogenous Activin A is sufficient to induce developmental gene expression and morphological defects in wild-type BEC organoids, while early postnatal inhibition of Activin A in vivo rescues IHBD morphogenesis in the absence of Sox9 . Our data demonstrate that proper IHBD architecture relies on inhibition of Activin A by Sox9 to promote ductule morphogenesis, defining regulatory mechanisms underlying morphological heterogeneity. The bile ducts of the liver form a network of large ducts and small ductules, though how they are patterned remains unclear. Hrncir et al. show that Sox9 is required for the morphogenesis of small intrahepatic bile ductules in mice, highlighting distinct genetic requirements that drive bile duct heterogeneity.

BackgroundHepatectomy is a definitive treatment for hepatolithiasis because it simultaneously removes intrahepatic duct (IHD) stones and biliary tract strictures together with the involved liver region en bloc. Unlike cystic or solid liver tumors, hepatolithiasis is usually associated with alterations of anatomical structures and perihepatic adhesions because of chronic recurrent inflammation. This complicates identification of the target hepatic region and location of biliary strictures.MethodsTo determine the efficacy of near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG), we performed a comparative trial and developed a white-light and near-infrared dual-channel image-guided device (DPM-I) for both open and endoscopic surgery. Forty-four eligible patients were randomly assigned to Group A (NIRF imaging) or Group B (traditional hepatectomy). We injected ICG via peripheral veins for patients in Group A.ResultsThe NIRF imaging method was associated with less blood loss (OR 1.004, 95% CI 0.999–1.010; P = 0.016), briefer hospitalization (OR 1.336, 95% CI 1.016–1.756; P = 0.001), lower rates of margins with dilated bile ducts (OR 1.278, 95% CI 1.030–1.585; P = 0.023), lower postoperative white blood cell counts (OR 1.262, 95% CI 0.931–1.712; P = 0.038), lower procalcitonin levels (OR 1.316, 95% CI 1.020–1.513; P = 0.002), and lower alanine aminotransferase levels (OR 1.013, 95% CI 1.003–1.023; P = 0.002) compared with traditional hepatectomy.ConclusionsThese data demonstrate the efficacy of NIRF imaging with ICG using DPM-I for treating hepatolithiasis.