Cholangiocarcinoma (CCA) is a fatal malignancy with steadily increasing incidence and poor prognosis. Since most CCA cases are diagnosed at an advanced stage, systemic therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, play a crucial role in the management of unresectable CCA. The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA. This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA, summarizes crucial clinical trials, and describes the efficacy and safety of different drugs, which may help further develop precision and individualization in the clinical treatment of unresectable CCA.
Humans ; Cholangiocarcinoma/drug therapy* ; Immunotherapy/methods* ; Bile Duct Neoplasms/drug therapy* ; Molecular Targeted Therapy/methods*

Cholangiocarcinoma (CCA) is a malignant tumor originating from cholangiocytes. However, it remains unclear about the pathogenesis of this carcinoma, which may be related to multiple factors. Currently, CCA is mainly treated by surgery, chemotherapy, and radiotherapy. Among them, surgery is the only potentially curative option for CCA. Nevertheless, the high malignancy and asymptomatic nature of CCA may lead to poor treatment outcomes. It has been demonstrated that Chinese medicine (CM) plays a significant role in various antitumor applications. Meanwhile, CM exhibits fewer side effects and high availability. Moreover, the in vitro application of CM monomers has been explored in many domestic and foreign studies. This article mainly reviews the signaling pathways and molecular mechanisms of CM monomers in the treatment of CCA in recent years. These findings are expected to provide new insights into the treatment of CCA.
Cholangiocarcinoma/drug therapy* ; Humans ; Drugs, Chinese Herbal/pharmacology* ; Bile Duct Neoplasms/drug therapy* ; Medicine, Chinese Traditional ; Animals ; Signal Transduction/drug effects*

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder. Its occurrence secondary to hepatobiliary malignancies is even rarer, and without timely diagnosis and treatment, the mortality rate is extremely high. There is a need to raise awareness of this disease. This report describes a case of a 70-year-old female patient diagnosed with AHA 2 months after surgery for cholangiocarcinoma, admitted to the Second Affiliated Hospital of Bengbu Medical College in October 2022. The patient presented with subcutaneous hematoma in both lower limbs. Coagulation function tests showed a markedly prolonged activated partial thromboplastin time (APTT) of 74.5 seconds, with no correction in the APTT mixing test. Coagulation factor assays revealed a severely reduced coagulation factor VIII activity (FVIII:C) of 0.3%, and an inhibitor titer of 25.6 BU/mL was detected. After ruling out other potential causes, the patient was diagnosed with cholangiocarcinoma-associated AHA. With chemotherapy to control the primary tumor, alongside hemostatic and immunosuppressive therapy for inhibitor eradication, AHA was brought under control. The patient had no further coagulation abnormalities or bleeding, enabling timely and full-course chemotherapy for cholangiocarcinoma and significantly improving survival and quality of life. Therefore, in patients with malignancies who present with spontaneous bleeding or unusual bleeding following surgery, trauma, or invasive procedures, clinicians should be alert to the possibility of secondary AHA. Timely diagnosis and treatment can significantly improve prognosis.
Humans ; Cholangiocarcinoma/surgery* ; Female ; Hemophilia A/drug therapy* ; Aged ; Bile Duct Neoplasms/surgery* ; Factor VIII

Primary neuroendocrine tumors originating from the extrahepatic bile duct are rare. Among these tumors, large cell neuroendocrine carcinomas (NECs) are extremely rare. A 59-year-old man was admitted to Sanggye Paik Hospital with jaundice that started 10 days previously. He had a history of laparoscopic cholecystectomy, which he had undergone 12 years previously due to chronic calculous cholecystitis. Laboratory data showed abnormally elevated levels of total bilirubin 15.3 mg/dL (normal 0.2–1.2 mg/dL), AST 200 IU (normal 0–40 IU), ALT 390 IU (normal 0–40 IU), and gamma-glutamyl transferase 1,288 U/L (normal 0–60 U/L). Serum CEA was normal, but CA 19-9 was elevated 5,863 U/mL (normal 0–37 U/mL). Abdominal CT revealed a 4.5 cm sized mass involving the common bile duct and liver hilum and dilatation of both intrahepatic ducts. Percutaneous transhepatic drainage in the left hepatic duct was performed for preoperative biliary drainage. The patient underwent radical common bile duct and Roux-en-Y hepaticojejunostomy for histopathological diagnosis and surgical excision. On histopathological examination, the tumor exhibited large cell NEC (mitotic index >20/10 high-power field, Ki-67 index >20%, CD56 [+], synaptophysin [+], chromogranin [+]). Adjuvant concurrent chemotherapy and radiotherapy were started because the tumor had invaded the proximal resection margin. No recurrence was detected at 10 months by follow-up CT.
Bile Duct Neoplasms ; Bile Ducts, Extrahepatic* ; Bilirubin ; Carcinoma, Neuroendocrine* ; Cholecystectomy, Laparoscopic ; Cholecystitis ; Common Bile Duct ; Diagnosis ; Dilatation ; Drainage ; Drug Therapy ; Follow-Up Studies ; Hepatic Duct, Common ; Humans ; Jaundice ; Liver ; Middle Aged ; Neuroendocrine Tumors ; Radiotherapy ; Recurrence ; Synaptophysin ; Tomography, X-Ray Computed ; Transferases

A 54-year-old female with postprandial dyspepsia and abdominal pain was diagnosed as locally advanced unresectable intrahepatic cholangiocarcinoma by radiologic imaging studies resulting in invasion to bilateral main bile duct and right portal vein. The patient underwent extended right hepatectomy and portal vein resection after gemcitabine and cisplatin combined chemotherapy for a total of 40 cycles after the diagnosis. Final pathology showed, followed by pathological complete remission, without any residual cancer cell. The patient has survived for over 6 years without any evidence of recurrence. This case suggests that locally advanced intrahepatic cholangiocarcinoma, which can't be resected, was also proved to be capable of pathological complete remission with active chemotherapy, and long-term survival could be achieved. Therefore, active multidisciplinary approach and patient-oriented treatments using various methods should be considered for locally advanced unresectable intrahepatic cholangiocarcinoma.
Abdominal Pain ; Bile Duct Neoplasms ; Bile Ducts ; Cholangiocarcinoma* ; Cisplatin ; Diagnosis ; Drug Therapy* ; Dyspepsia ; Female ; Hepatectomy ; Humans ; Middle Aged ; Neoplasm, Residual ; Pathology ; Portal Vein ; Recurrence

A 56-year-old man was diagnosed with cancer of the ascending colon along with retroperitoneal lymph node and peritoneal metastases. After six cycles of palliative chemotherapy, he presented with acute-onset jaundice. Imaging examinations did not show abnormal liver findings other than a periportal linear hypoattenuating area, and endoscopic retrograde cholangiography revealed a tight stricture of the proximal common bile duct. Total bilirubin continued to increase after endoscopic sphincterotomy and biliary stent insertion. Blind liver biopsy revealed tumor infiltration along liver lymphatics, but ruled out tumor involvement of hepatic parenchyma and sinusoids. Tumor cells were predominantly confined to within the lymphatic vessels and were not observed in the arteries or veins. Although one loading dose of cetuximab and two fractions of palliative radiotherapy were administered, the patient succumbed to acute liver injury 30 days after the development of jaundice.
Arteries ; Bilirubin ; Biopsy ; Cetuximab ; Cholangiography ; Colon* ; Colon, Ascending ; Colonic Neoplasms* ; Common Bile Duct ; Constriction, Pathologic ; Drug Therapy ; Humans ; Jaundice ; Liver* ; Lymph Nodes ; Lymphatic Metastasis ; Lymphatic Vessels ; Middle Aged ; Neoplasm Metastasis* ; Radiotherapy ; Sphincterotomy, Endoscopic ; Stents ; Veins

BACKGROUND/AIMS: Statins act as antineoplastic agents through the inhibition of cell proliferation. This study sought to demonstrate the effects of statins on extrahepatic bile duct cancer cell apoptosis and to document the changes in protein expression involved in tumor growth and suppression. METHODS: Human extrahepatic bile duct cancer cells were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of statins on cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and caspase-3 activity assay, and flow cytometry was used to determine the percentage of cells in each phase of the cell cycle. The protein expression of Bax, Bcl-2, insulin-like growth factor 1 (IGF-1) receptor, extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt was measured by Western blot analysis. RESULTS: Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation. CONCLUSIONS: Simvastatin induces apoptosis in bile duct cancer cells, which suggests that it could be an antineoplastic agent for bile duct cancer.
Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Bile Duct Neoplasms/*drug therapy ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Hypolipidemic Agents/*pharmacology ; Receptor, IGF Type 1/*drug effects ; Simvastatin/*pharmacology

In the palliative setting, the necessity of biliary drainage of both liver lobes for malignant hilar biliary obstruction remains controversial. However, bilateral biliary drainage is a reasonable option to prevent cholangitis of the undrained lobe and to preserve liver function during the course of chemotherapy. Bilateral biliary drainage can be accomplished by the percutaneous or endoscopic placement of multiple self-expandable metallic stents (SEMS). Although SEMS placement via bilateral (multiple) percutaneous routes is technically simple, multiple percutaneous transhepatic biliary drainage (PTBD) may lead to additional morbidity. SEMS placement via a single percutaneous route is a useful method; however, negotiation of a guidewire into the contralateral bile duct is occasionally impossible if the hilar angle between the right hepatic duct and left hepatic duct is acute. Percutaneous dual SEMS placement is generally performed using the stent-in-stent technique (T configuration or Y configuration) or the side-by-side technique. In addition, the crisscross technique has been reported as being a useful method for trisegmental drainage. The side-to-end technique is also useful for multiple SEMS placement. In the future, the combination of percutaneous intervention and endoscopic ultrasonography-guided procedures may be effective in the management of malignant hilar biliary obstruction.
Bile Ducts ; Biliary Tract Neoplasms ; Cholangitis ; Drainage ; Drug Therapy ; Hepatic Duct, Common ; Liver ; Methods ; Negotiating ; Stents*

Ovarian metastases represent about 3-5% of all ovarian malignancies. Most of these tumors originate in the digestive tract and cholangiocarcinoma rarely involves the ovary. A 60-year-old woman was admitted for the investigation of abdominal distension that had lasted 1 week. One and a half years prior, the patient had undergone choledochal cyst excision, Roux-en Y hepaticojejunostomy and cholecystectomy. Computed tomography scans of the abdomen revealed a papillary mass in the remnant distal common bile duct and enlargement of both ovaries with a huge amount of ascites. An explorative laparotomy disclosed no peritoneal seeding with resectable cholangiocarcinoma and bilateral ovarian mass. Pylorus-preserving pancreatoduodenectomy and bilateral salphingo-oophorectomy with hysterectomy were performed. Histologically, it was a well-differentiated adenocarcinoma and all surgical margins were free of tumor. Both ovarian masses were consistent with metastatic adenocarcinoma from the common bile duct. The patient received six cycles of postoperative adjuvant systemic chemotherapy, dying after 10 months due to pulmonary embolism.
Abdomen ; Adenocarcinoma ; Ascites ; Cholangiocarcinoma ; Cholecystectomy ; Choledochal Cyst* ; Common Bile Duct* ; Drug Therapy ; Female ; Gastrointestinal Tract ; Humans ; Hysterectomy ; Laparotomy ; Middle Aged ; Neoplasm Metastasis* ; Ovarian Neoplasms ; Ovary ; Pancreaticoduodenectomy ; Pulmonary Embolism

The patient was a 70-year-old male whose chief complaints were obstructive jaundice and weight loss. Abdominal imaging studies showed a 2.5 cm sized mass at the distal common bile duct, which was suggestive of bile duct cancer. Eccentric enhancing wall thickening in the transverse colon was also shown, suggesting concomitant colon cancer. A colonoscopy revealed a lumen-encircling ulcerofungating mass in the transverse colon, that was pathologically proven to be adenocarcinoma. The bile duct pathology was also adenocarcinoma. Pylorus-preserving pancreaticoduodenectomy and extended right hemicolectomy were performed under the diagnosis of double primary cancers. Postoperative histopathologic examination revealed moderately differentiated mucinous adenocarcinoma of transverse colon cancer, and mucinous adenocarcinoma of the distal common bile duct. Immunohistochemical staining studies showed that the bile duct cancer had metastasized from the colon cancer. The patient recovered uneventfully from surgery and will be undergoing chemotherapy for three months.
Adenocarcinoma ; Adenocarcinoma, Mucinous* ; Aged ; Bile Duct Neoplasms ; Bile Ducts ; Colon, Transverse* ; Colonic Neoplasms ; Colonoscopy ; Common Bile Duct Neoplasms ; Common Bile Duct* ; Diagnosis ; Drug Therapy ; Humans ; Jaundice, Obstructive* ; Male ; Mucins* ; Neoplasm Metastasis ; Pancreaticoduodenectomy ; Pathology ; Weight Loss