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ESMO Open Feb 2022Management of biliary tract cancers (BTCs) is rapidly evolving. Curative management relies on surgical resection followed by adjuvant capecitabine for cholangiocarcinoma... (Review)
Review
Management of biliary tract cancers (BTCs) is rapidly evolving. Curative management relies on surgical resection followed by adjuvant capecitabine for cholangiocarcinoma and gallbladder cancers. Unfortunately relapse rate remains high, and better adjuvant strategies are urgently required. A majority of patients are diagnosed with advanced disease, when chemotherapy with cisplatin and gemcitabine followed by second-line 5-FU and oxaliplatin /irinotecan is the cornerstone of treatment for most patients in the absence of targetable alterations. Targeted therapies, including therapies for tumours with fibroblast growth factor receptor-2 (FGFR-2) fusions, isocitrate dehydrogenase-1 (IDH-1) mutations, B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions, Human epidermal growth factor-2 (HER-2) amplifications, and/or microsatellite instability are rapidly changing the treatment paradigm for many patients with advanced BTC, especially for patients with intrahepatic cholangiocarcinoma. Because of this, molecular profiling should be considered early on patients pathway to allow adequate planning of therapy. Ongoing research is likely to clarify the role of immunotherapy, liver-directed therapy, and liver transplant for BTCs in the future.
Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biliary Tract Neoplasms; Cholangiocarcinoma; Humans; Neoplasm Recurrence, Local
PubMed: 35032765
DOI: 10.1016/j.esmoop.2021.100378 -
Journal of Visceral Surgery Dec 2019Acute cholangitis is an infection of the bile and biliary tract which in most cases is the consequence of biliary tract obstruction. The two main causes are... (Review)
Review
Acute cholangitis is an infection of the bile and biliary tract which in most cases is the consequence of biliary tract obstruction. The two main causes are choledocholithiasis and neoplasia. Clinical diagnosis relies on Charcot's triad (pain, fever, jaundice) but the insufficient sensitivity of the latter led to the introduction in 2007 of a new score validated by the Tokyo Guidelines, which includes biological and radiological data. In case of clinical suspicion, abdominal ultrasound quickly explores the biliary tract, but its diagnostic capacities are poor, especially in case of non-gallstone obstruction, as opposed to magnetic resonance cholangiopancreatography and endoscopic ultrasound, of which the diagnostic capacities are excellent. CT scan is more widely available, with intermediate diagnostic capacities. Bacteriological sampling through blood cultures (positive in 40% of cases) and bile cultures is essential. A wide variety of bacteria are involved, but the main pathogens having been found are Escherichia coli and Klebsiella spp., justifying first-line antimicrobial therapy by a third-generation cephalosporin. Systematic coverage of Enterococcus spp. and anaerobic infections remains debated, and is usually recommended, in case of severity criteria for Enterococcus severity levels, or anaerobic bilio-digestive anastomosis for anaerobes. Presence of a biliary stent is the only identified risk-factor associated with infections by multidrug-resistant pathogens. Along with antimicrobial therapy, endoscopic or radiological biliary drainage is a crucial management component. Despite improved management, mortality in cases of acute cholangitis remains approximately 5%.
Topics: Abdominal Pain; Acute Disease; Algorithms; Anti-Bacterial Agents; Biliary Tract; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis; Cholestasis; Drainage; Fever; Humans; Jaundice; Prognosis; Severity of Illness Index
PubMed: 31248783
DOI: 10.1016/j.jviscsurg.2019.05.007 -
Annals of Hepatology 2022Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it... (Review)
Review
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
Topics: Bile Duct Neoplasms; Bile Ducts, Extrahepatic; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Humans; Klatskin Tumor
PubMed: 35809836
DOI: 10.1016/j.aohep.2022.100737 -
Annals of Oncology : Official Journal... Feb 2023
Topics: Humans; Follow-Up Studies; Biliary Tract Neoplasms; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Gallbladder Neoplasms
PubMed: 36372281
DOI: 10.1016/j.annonc.2022.10.506 -
Journal of Gastroenterology and... Jun 2020Distal biliary strictures (DBS) are common and may be caused by both malignant and benign pathologies. While endoscopic procedures play a major role in their management,... (Review)
Review
Distal biliary strictures (DBS) are common and may be caused by both malignant and benign pathologies. While endoscopic procedures play a major role in their management, a comprehensive review of the subject is still lacking. Our consensus statements were formulated by a group of expert Asian pancreatico-biliary interventional endoscopists, following a proposal from the Digestive Endoscopy Society of Taiwan, the Thai Association for Gastrointestinal Endoscopy, and the Tokyo Conference of Asian Pancreato-biliary Interventional Endoscopy. Based on a literature review utilizing Medline, Cochrane library, and Embase databases, a total of 19 consensus statements on DBS were made on diagnosis, endoscopic drainage, benign biliary stricture, malignant biliary stricture, and management of recurrent biliary obstruction and other complications. Our consensus statements provide comprehensive guidance for the endoscopic management of DBS.
Topics: Asian People; Biliary Tract; Biliary Tract Surgical Procedures; Cholestasis; Consensus; Constriction, Pathologic; Endoscopy, Digestive System; Gastroenterology; Humans; International Cooperation; Societies, Medical; Taiwan; Tokyo
PubMed: 31802537
DOI: 10.1111/jgh.14955 -
Science (New York, N.Y.) Feb 2021The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain...
The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2-mechanistic target of rapamycin-cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration.
Topics: Animals; Biliary Tract; Biliary Tract Diseases; Cell Proliferation; Cyclin D1; Gene Knock-In Techniques; Hepatocytes; Homeostasis; Insulin-Like Growth Factor Binding Protein 2; Liver; Liver Regeneration; Mice; TOR Serine-Threonine Kinases
PubMed: 33632817
DOI: 10.1126/science.abb1625 -
Nature Oct 2019Organogenesis is a complex and interconnected process that is orchestrated by multiple boundary tissue interactions. However, it remains unclear how individual,...
Organogenesis is a complex and interconnected process that is orchestrated by multiple boundary tissue interactions. However, it remains unclear how individual, neighbouring components coordinate to establish an integral multi-organ structure. Here we report the continuous patterning and dynamic morphogenesis of hepatic, biliary and pancreatic structures, invaginating from a three-dimensional culture of human pluripotent stem cells. The boundary interactions between anterior and posterior gut spheroids differentiated from human pluripotent stem cells enables retinoic acid-dependent emergence of hepato-biliary-pancreatic organ domains specified at the foregut-midgut boundary organoids in the absence of extrinsic factors. Whereas transplant-derived tissues are dominated by midgut derivatives, long-term-cultured microdissected hepato-biliary-pancreatic organoids develop into segregated multi-organ anlages, which then recapitulate early morphogenetic events including the invagination and branching of three different and interconnected organ structures, reminiscent of tissues derived from mouse explanted foregut-midgut culture. Mis-segregation of multi-organ domains caused by a genetic mutation in HES1 abolishes the biliary specification potential in culture, as seen in vivo. In sum, we demonstrate that the experimental multi-organ integrated model can be established by the juxtapositioning of foregut and midgut tissues, and potentially serves as a tractable, manipulatable and easily accessible model for the study of complex human endoderm organogenesis.
Topics: Animals; Biliary Tract; Biomarkers; Body Patterning; Endoderm; Humans; Induced Pluripotent Stem Cells; Intestines; Liver; Male; Mice; Models, Biological; Morphogenesis; Organoids; Pancreas; Spheroids, Cellular; Transcription Factor HES-1
PubMed: 31554966
DOI: 10.1038/s41586-019-1598-0 -
Current Oncology (Toronto, Ont.) Sep 2021Ampullary carcinomas (ACs) represent a rare entity, accounting for approximately 0.2% of all gastrointestinal solid tumors and 20% of all periampullary cancers (PACs).... (Review)
Review
Ampullary carcinomas (ACs) represent a rare entity, accounting for approximately 0.2% of all gastrointestinal solid tumors and 20% of all periampullary cancers (PACs). Unfortunately, few data are available regarding the optimal therapeutic strategy for ACs due to their rarity, and physicians frequently encounter significant difficulties in the management of these malignancies. In this review, we will provide an overview of current evidence on AC, especially focusing on biological features, histological characteristics, and available data guiding present and future therapeutic strategies for these rare, and still barely known, tumors.
Topics: Adenocarcinoma; Ampulla of Vater; Common Bile Duct Neoplasms; Humans
PubMed: 34590592
DOI: 10.3390/curroncol28050293 -
Hepatology (Baltimore, Md.) Apr 2024Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly... (Review)
Review
Cholangiocarcinoma (CCA) comprises diverse tumors of the biliary tree and is characterized by late diagnosis, short-term survival, and chemoresistance. CCAs are mainly classified according to their anatomical location and include diverse molecular subclasses harboring inter-tumoral and intratumoral heterogeneity. Besides the tumor cell component, CCA is also characterized by a complex and dynamic tumor microenvironment where tumor cells and stromal cells crosstalk in an intricate network of interactions. Cancer-associated fibroblasts, one of the most abundant cell types in the tumor stroma of CCA, are actively involved in cholangiocarcinogenesis by participating in multiple aspects of the disease including extracellular matrix remodeling, immunomodulation, neo-angiogenesis, and metastasis. Despite their overall tumor-promoting role, recent evidence indicates the presence of transcriptional and functional heterogeneous CAF subtypes with tumor-promoting and tumor-restricting properties. To elucidate the complexity and potentials of cancer-associated fibroblasts as therapeutic targets in CCA, this review will discuss the origin of cancer-associated fibroblasts, their heterogeneity, crosstalk, and role during tumorigenesis, providing an overall picture of the present and future perspectives toward cancer-associated fibroblasts targeting CCA.
Topics: Humans; Cancer-Associated Fibroblasts; Cholangiocarcinoma; Biliary Tract; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Tumor Microenvironment; Contracture; Arachnodactyly
PubMed: 37018128
DOI: 10.1097/HEP.0000000000000206 -
Journal of Hepatology Sep 2021Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found...
BACKGROUND & AIMS
Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis.
METHODS
TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4, Abcb4/Tgr5 and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4 mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models.
RESULTS
TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4 livers, in Abcb4 extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4 mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4 BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4 livers.
CONCLUSIONS
Reduced TGR5 levels in BECs from patients with PSC and Abcb4 mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA.
LAY SUMMARY
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells.
Topics: Animals; Biliary Tract; Cholangitis, Sclerosing; Disease Models, Animal; Down-Regulation; Epithelial Cells; Liver; Mice; Receptors, G-Protein-Coupled; Virulence Factors
PubMed: 33872692
DOI: 10.1016/j.jhep.2021.03.029