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European Journal of Cancer (Oxford,... May 2024For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options... (Review)
Review
For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options available for patients with unresectable BTC have drastically increased, with immunotherapy and targeted treatment gradually joining the ranks of guideline-recommended treatment regimens. The aim of the present review is to summarise the current knowledge on unresectable BTC focusing on epidemiology, anatomical distribution and current strategies for systemic treatment. We further outline ongoing clinical trials and provide an outlook on future therapeutic interventions. In the realm of gastrointestinal malignancies, the increasing number of systemic treatment options for BTC is finally delivering on the longstanding commitment to personalised oncology. This emphasises the need for considering a comprehensive genomic-based pathology assessment right from the initial diagnosis to fully leverage the expanding array of therapeutic options that have recently become accessible.
Topics: Humans; Biliary Tract Neoplasms; Immunotherapy; Molecular Targeted Therapy
PubMed: 38626513
DOI: 10.1016/j.ejca.2024.114046 -
World Journal of Gastroenterology Mar 2024Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common... (Review)
Review
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
Topics: Infant; Child; Infant, Newborn; Humans; Bile Ducts; Biliary Atresia; Choledochal Cyst; Bile Duct Diseases; Cholangiography
PubMed: 38577180
DOI: 10.3748/wjg.v30.i9.1043 -
World Journal of Gastroenterology Oct 2023Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that is observed more frequently in middle-aged women. This disorder is considered an autoimmune... (Review)
Review
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that is observed more frequently in middle-aged women. This disorder is considered an autoimmune disease, since liver injury is sustained by the presence of self-directed antimitochondrial antibodies targeting the bile duct cells. The prognosis may vary depending on an early diagnosis and response to therapy. However, nearly a third of patients can progress to liver cirrhosis, thus requiring a liver transplant. Traditional immunosuppressive therapies, commonly employed for other autoimmune diseases, have limited effects on PBC. In fact, dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury. In this minireview, after a background on the disease and possible predisposing factors, the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail. The rise and maintenance of the autoimmune process, as well as the response of the biliary epithelia during inflammatory injury, are key factors in the progression of the disease. The so-called "ductular reaction (DR)", intended as a reactive expansion of cells with biliary phenotype, is a process frequently observed in PBC and partially understood. However, recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis, cell senescence, and loss of biliary ducts. All these issues (onset of chronic inflammation, changes in secretive and proliferative biliary functions, DR, and its relationship with other pathological events) are discussed in this manuscript in an attempt to provide a snapshot, for clinicians and researchers, of the most relevant and sequential contributors to the progression of this human cholestatic disease. We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.
Topics: Middle Aged; Humans; Female; Liver Cirrhosis, Biliary; Bile Ducts; Liver Cirrhosis; Cholestasis; Autoimmune Diseases; Inflammation; Cholangitis
PubMed: 37899786
DOI: 10.3748/wjg.v29.i37.5305 -
Medicina (Kaunas, Lithuania) Jun 2023Cholangiocarcinoma (CCA) is an invasive cancer accounting for <1% of all cancers and 10-15% of primary liver cancers. Intrahepatic CCA (iCCA) is associated with poor... (Review)
Review
Cholangiocarcinoma (CCA) is an invasive cancer accounting for <1% of all cancers and 10-15% of primary liver cancers. Intrahepatic CCA (iCCA) is associated with poor survival rates and high post-surgical recurrence rates whilst most diagnosed patients are not surgical candidates. There is a growing literature suggesting percutaneous ablative techniques for the management of patients with iCCA measuring ≤3 cm with contraindications to surgery as well as for recurrent or residual tumors aiming to provide local cancer treatment and control. Most used ablative therapies for iCCA include radiofrequency and microwave ablation with irreversible electroporation, cryoablation and reversible electroporation (electrochemotherapy) being less commonly encountered techniques. Due to the infiltrative margins of the lesion, there is a need for larger safety margins and ablation zone; multi-apparatus ablation or other variations of the technique such as balloon-assisted approaches can be utilized aiming to increase size of the zone of necrosis. The present review paper focuses upon the current role of percutaneous ablative techniques for the therapeutic management of iCCA. The purpose of this review is to present the current minimally invasive ablative techniques in the treatment of iCCA, including local control and survival rates.
Topics: Humans; Cholangiocarcinoma; Cryosurgery; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Catheter Ablation
PubMed: 37511998
DOI: 10.3390/medicina59071186 -
Frontiers in Cellular and Infection... 2023Endoscopic retrograde cholangiopancreatography (ERCP) is an effective minimally invasive operation for the management of choledocholithiasis, while successful extraction...
BACKGROUND
Endoscopic retrograde cholangiopancreatography (ERCP) is an effective minimally invasive operation for the management of choledocholithiasis, while successful extraction is hampered by large diameter of stones. Emerging studies have revealed the close correlation between biliary microbiota and common bile duct stones (CBDS). In this study, we aimed to investigate the community characteristics and metabolic functions of biliary microbiota in patients with giant CBDS.
METHODS
Eligible patients were prospectively enrolled in this study in First Affiliated Hospital of Soochow University from February 2022 to October 2022. Bile samples were collected through ERCP. The microbiota was analyzed using 16S rRNA sequencing. Metabolic functions were predicted by PICRUSTs 2.0 calculation based on MetaCyc database. Bile acids were tested and identified using ultra performance liquid chromatography-tandem mass spectrometry.
RESULTS
A total of 26 patients were successfully included into final analysis, 8 in giant stone (GS) group and 18 in control group. Distinct biliary microbial composition was identified in patients with giant CBDS, with a significantly higher abundance of Firmicutes at phylum level. The unique composition at genus level mainly consisted of Enterococcus, Citrobacter, Lactobacillus, Pyramidobacter, Bifidobacterium and Shewanella. Pyramidobacter was exclusively found in GS group, along with the absence of Robinsoniella and Coprococcus. The contents of free bile acids were significantly higher in GS group, including cholic acid (98.39μmol/mL vs. 26.15μmol/mL, =0.035), chenodesoxycholic acid (54.69μmol/mL vs. 5.86μmol/mL, =0.022) and ursodeoxycholic acid (2.70μmol/mL vs. 0.17μmol/mL, =0.047). Decreasing tendency of conjugated bile acids were also observed. Metabolic pathways concerning cholelithiasis were abundant in GS group, including geranylgeranyl diphosphate biosynthesis, gluconeogenesis, glycolysis and L-methionine biosynthesis.
CONCLUSIONS
This study demonstrated the community structure and metabolic potential of biliary microbiota in patients with giant CBDS. The unique biliary microbial composition holds valuable predictive potential for clinical conditions. These findings provide new insights into the etiology of giant CBDS from the perspective of biliary microbiota.
Topics: Humans; RNA, Ribosomal, 16S; Gallstones; Common Bile Duct; Microbiota; Bile Acids and Salts
PubMed: 38029241
DOI: 10.3389/fcimb.2023.1259761 -
Nature Reviews. Gastroenterology &... Jul 2023Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging,... (Review)
Review
Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
Topics: Humans; Bile Duct Neoplasms; Cholangiocarcinoma; Consensus; Bile Ducts, Intrahepatic
PubMed: 36755084
DOI: 10.1038/s41575-022-00739-y -
Frontiers in Immunology 2023The relationship between the tumor microenvironment and the network of key signaling pathways in cancer plays a key role in the occurrence and development of tumors....
BACKGROUND AND OBJECTIVES
The relationship between the tumor microenvironment and the network of key signaling pathways in cancer plays a key role in the occurrence and development of tumors. Tumor-associated macrophages (TAMs) are important inflammatory cells in the tumor microenvironment and play an important role in tumorigenesis and progression. Macrophages in malignant tumors, mainly the M2 subtype, promote tumor progression by producing cytokines and down-regulating anti-inflammatory immune responses. Several articles have investigated the effect of macrophages on the sensitivity of cancer chemotherapeutic agents, but few such articles have been reported in cholangiocarcinoma, so we investigated the effect of M2 macrophage on the sensitivity of cholangiocarcinoma cells to Lenvatinib compared to M1.
METHODS
THP-1 monocytes were polarized to M0 macrophage by phorbol 12-myristate 13-acetate (PMA) and then induced to differentiate into M1 and M2 macrophages by LPS, IFN-γ and IL-4 and IL-13, respectively. Macrophages and cholangiocarcinoma cells were co-cultured prior to 24 hours of Lenvatinib administration, cancer cell apoptosis was detected by western-blot, FACS analysis of Annexin V and PI staining. Furthermore, we use xCELLigence RTCA SP Instrument (ACEA Bio-sciences) to monitor cell viability of Lenvatinib administration in co-culture of cholangiocarcinoma cells and macrophages. After tumorigenesis in immunodeficient mice, Lenvatinib was administered, and the effects of M2 on biological characteristics of cholangiocarcinoma cells were investigated by immuno-histochemistry.
RESULTS
mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1 derived macrophages, which provided a successful and efficient model of monocyte polarization to TAMs. Lenvatinib-induced apoptosis of cholangiocarcinoma cells was significantly reduced when co-cultured with M2 macrophage, whereas apoptosis of cholangiocarcinoma cells co-cultured with M1 macrophage was increased. In the CDX model, Lenvatinib-induced cancer cell apoptosis was markedly reduced, and proliferative cells increased in the presence of M2 macrophages. Angiogenesis related factors was significantly increased in cholangiocarcinoma cells co-cultured with M2.
CONCLUSION
Compared with M1, M2 macrophages can inhibit the anti-tumor effect of Lenvatinib on cholangiocarcinoma through immune regulation, which may be related to the tumor angiogenesis factor effect of M2 macrophage.
Topics: Animals; Mice; Macrophages; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Tumor Microenvironment
PubMed: 37809069
DOI: 10.3389/fimmu.2023.1251648 -
Microorganisms Sep 2023Cancers of the biliary tract are more common in Asia than in Europe, but are highly lethal due to delayed diagnosis and aggressive tumor biology. Since the biliary tract... (Review)
Review
Cancers of the biliary tract are more common in Asia than in Europe, but are highly lethal due to delayed diagnosis and aggressive tumor biology. Since the biliary tract is in direct contact with the gut via the enterohepatic circulation, this suggests a potential role of gut microbiota, but to date, the role of gut microbiota in biliary tract cancers has not been elucidated. This scoping review compiles recent data on the associations between the gut microbiota and diagnosis, progression and prognosis of biliary tract cancer patients. Systematic review of the literature yielded 154 results, of which 12 studies and one systematic review were eligible for evaluation. The analyses of microbiota diversity indices were inconsistent across the included studies. In-depth analyses revealed differences between gut microbiota of biliary tract cancer patients and healthy controls, but without a clear tendency towards particular species in the studies. Additionally, most of the studies showed methodological flaws, for example non-controlling of factors that affect gut microbiota. At the current stage, there is a lack of evidence to support a general utility of gut microbiota diagnostics in biliary tract cancers. Therefore, no recommendation can be made at this time to include gut microbiota analyses in the management of biliary tract cancer patients.
PubMed: 37764207
DOI: 10.3390/microorganisms11092363 -
Developmental Cell Dec 2023The extrahepatic branches of the biliary tree have glands that connect to the surface epithelium through narrow pits. The duct epithelia undergo homeostatic renewal, yet...
The extrahepatic branches of the biliary tree have glands that connect to the surface epithelium through narrow pits. The duct epithelia undergo homeostatic renewal, yet the identity and multiplicity of cells that maintain this tissue is unknown. Using marker-free and targeted clonal fate mapping in mice, we provide evidence that the extrahepatic bile duct is compartmentalized. Pit cholangiocytes of extramural glands renewed the surface epithelium, whereas basally oriented cholangiocytes maintained the gland itself. In contrast, basally positioned cholangiocytes replenished the surface epithelium in mural glands. Single-cell sequencing identified genes enriched in the base and surface epithelial populations, with trajectory analysis showing graded gene expression between these compartments. Epithelia were plastic, changing cellular identity upon fasting and refeeding. Gain of canonical Wnt signaling caused basal cell expansion, gastric chief cell marker expression, and a decrease in surface epithelial markers. Our results identify the cellular hierarchy governing extrahepatic biliary epithelial renewal.
Topics: Animals; Mice; Biliary Tract; Bile Ducts, Extrahepatic; Epithelium; Epithelial Cells; Cell Proliferation
PubMed: 37909044
DOI: 10.1016/j.devcel.2023.10.004 -
The Oncologist Nov 2023Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors... (Review)
Review
Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors under investigation show reversible binding, and their activity is limited by acquired drug resistance. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor. Futibatinib stands out among FGFR inhibitors because of its covalent binding mechanism and low susceptibility to acquired resistance. Preclinical data indicated robust activity of futibatinib against acquired resistance mutations in the FGFR kinase domain. In early-phase studies, futibatinib showed activity in cholangiocarcinoma, and gastric, urothelial, breast, central nervous system, and head and neck cancers harboring various FGFR aberrations. Exploratory analyses indicated clinical benefit with futibatinib after prior FGFR inhibitor use. In a pivotal phase II trial, futibatinib demonstrated durable objective responses (42% objective response rate) and tolerability in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. A manageable safety profile was observed across studies, and patient quality of life was maintained with futibatinib treatment in patients with cholangiocarcinoma. Hyperphosphatemia, the most common adverse event with futibatinib, was well managed and did not lead to treatment discontinuation. These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches.
Topics: Humans; Quality of Life; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Protein Kinase Inhibitors; Receptor, Fibroblast Growth Factor, Type 1
PubMed: 37390492
DOI: 10.1093/oncolo/oyad149