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Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.Cholangiocytes, which line the intrahepatic and extrahepatic bile ducts, are specialized cells that regulate bile production and homeostasis. Here, the authors discuss the role of cholangiocytes in development and liver regeneration, inflammation and fibrosis and their interactions with the immune system.

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.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Agios Pharmaceuticals.

Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers. In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) with or without cetuximab (500 mg/m2), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149. Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52–74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43–65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1–7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7–6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1–13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6–16·0) in the chemotherapy alone group. The most common grade 3–4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group. The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option. Institut National du Cancer, Merck Serono.

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.

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality. Normothermic machine perfusion of the liver improved early graft function, demonstrated by reduced peak serum aspartate transaminase levels and early allograft dysfunction rates, and improved organ utilization and preservation times, although no differences were seen in graft or patient survival.

Objectives Role of 18-FDG PET/CT had been well established in other more prevalent malignancies such as colorectal and lung cancer; however, this is not as well defined in cholangiocarcinoma. Literature focusing on the prognostic values of preoperative PET/CT for resectable cholangiocarcinoma is scarce. Method This is a retrospective cohort of 66 consecutive patients who had received curative resection for cholangiocarcinoma from 2010 to 2015. All patients had preoperative 18-FDG PET/CT performed. Accuracy of metastatic lymph node detection of PET/CT and the prognostic value of maximum standard uptake value (SUV-max) was explored. Results There were 38 male and 28 female recruited, and the median age was 66. Intrahepatic cholangiocarcinoma (ICC) constituted the majority (59.1%) of the cases, followed by hilar cholangiocarcinoma (22.8%), gallbladder cancer (13.6%) and common bile duct cancer (4.5%). The 3-year disease-free survival (DFS) and overall survival (OS) of the whole population were 27.1 and 39.2%, respectively. The median follow-up duration was 27 months. The accuracy of PET/CT in metastatic lymph node detection was 72.7% ( P  = 0.005, 95% CI 0.583–0.871) and 81.8% ( P  = 0.011, 95% CI 0.635–0.990) in whole population and ICC subgroup analysis, respectively. SUV-max was shown by multivariate analysis to be an independent factor for DFS ( P  = 0.007 OR 1.16, 95% CI 1.04–1.29) and OS ( P  = 0.012 OR 1.145, 95% CI 1.030–1.273) after resection. SUV-max of 8 was shown to be a discriminant cut-off for poor oncological outcomes in patients with early cholangiocarcinoma (TNM stage I or II) after curative resection (3-year DFS: 21.2 vs. 63.2%, P  = 0.004, and 3-year OS: 29 vs. 74% P  = 0.048, respectively). Conclusion PET/CT is a reliable imaging modality for metastatic lymph node detection in cholangiocarcinoma. Tumour SUV-max is an independent factor for oncological outcomes in patients with resectable disease. For patients who have TNM stage I or II cholangiocarcinoma, tumour SUV-max over 8 is associated with significantly inferior disease-free and overall survival even after curative resection.

PurposeThis study aimed to establish a nomogram based on preoperative magnetic resonance imaging (MRI) features to predict the very early recurrence (VER, less than 6 months) of intrahepatic mass-forming cholangiocarcinoma (IMCC) after R0 resection.MethodsThis study enrolled a group of 193 IMCC patients from our institution between March 2010 and January 2022. Patients were allocated into the development cohort (n = 137) and the validation cohort (n = 56), randomly, and the preoperative clinical and MRI features were collected. Univariate and multivariate stepwise logistic regression assessments were adopted to assess predictors of VER. Nomogram was constructed and certificated in the validation cohort. The performance of the prediction nomogram was evaluated by its discrimination, calibration, and clinical utility. The performance of the nomogram was compared with the T stage of the American Joint Committee on Cancer (AJCC) 8th edition staging system.ResultsFifty-three patients (27.5%) experienced VER of the tumor and 140 patients (72.5%) with non-VER, during the follow-up period. After multivariate stepwise logistic regression, number of lesions, diffuse hypoenhancement on arterial phase, necorsis and suspicious lymph nodes were independently associated with VER. The nomogram demonstrated significantly higher area under the curve (AUC) of 0.813 than T stage (AUC = 0.666, P = 0.006) in the development cohort, whereas in the validation cohort, the nomogram showed better discrimination performance, with an AUC of 0.808 than T stage (0.705) with no significantly difference (P = 0.230). Decision curve analysis reflected the clinical net benefit of the nomogram.ConclusionThe nomogram based on preoperative MRI features is a reliable tool to predict VER for patients with IMCC after R0 resection. This nomogram will be helpful to improve survival prediction and individualized treatment.

We report the recent observation of a density duct structure in the equatorial plasmasphere, identified using data from the NASA Van Allen Probes (RBSP). The structure consists of a low‐density duct located above a high‐density duct, forming a “double duct” system capable of simultaneously trapping and guiding multiple whistler‐mode waves at distinct frequencies. Simulations based on the electron‐MHD model confirm that such density double ducts enable efficient confinement and propagation of whistler‐mode waves along the background magnetic field.

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.