Patient-derived organoids (PDOs) have been demonstrated to predict the response to drugs in multiple cancer types. However, it remains unclear about its application in cholangiocarcinoma.

A 59-year-old woman was admitted to the hospital due to upper abdominal pain for over 8 months. According to relevant examinations, she was diagnosed as perihilar cholangiocarcinoma (pCCA) with intrahepatic metastasis and perihilar lymphatic metastasis. After multidisciplinary team discussion, percutaneous transhepatic cholangiodrainage was performed to relieve biliary obstruction, and puncture biopsy was conducted to confirm the pathological diagnosis. Transarterial chemoembolization with nab-paclitaxel was used in combination with toripalimab and lenvatinib, but the levels of tumor markers including alpha fetal protein, carcinoembryonic antigen, carbohydrate antigen 15-3 and cancer antigen 125 were still raised. The PDO for drug screening showed sensitive to gemcitabine and cisplatin. Accordingly, the chemotherapy regimen was adjusted to gemcitabine and cisplatin in combination with toripalimab and lenvatinib. After 4 cycles of treatment, the tumor was assessed resectable, and radical surgical resection was performed successfully. One year after surgery, the patient was still alive, and no recurrence or occurred.

PDOs for drug sensitivity contribute to screening effective chemotherapy drugs for advanced pCCA, promoting conversion therapy and improving the prognosis.

• Patient-derived organoids
• Perihilar cholangiocarcinoma
• Conversion therapy
• Drug screening
• Intrahepatic metastasis
• Case report

• antibiotics
• chemotherapy
• cholangiocarcinoma
• cholangitis
• drug therapy

• Humans
• Male
• Female
• Aged
• Japan
• Biliary Tract Neoplasms/drug therapy
• Databases, Factual
• Middle Aged
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/therapeutic use
• Deoxycytidine/administration & dosage
• Gemcitabine
• Tegafur/administration & dosage
• Tegafur/therapeutic use
• Retrospective Studies
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Drug Combinations
• Cisplatin/therapeutic use
• Cisplatin/administration & dosage
• Oxonic Acid/administration & dosage
• Oxonic Acid/therapeutic use
• Practice Patterns, Physicians'/statistics & numerical data

• AstraZeneca K.K.

• Intrahepatic cholangiocarcinoma
• Neoadjuvant chemotherapy
• Pathological complete response

• diagnosis
• intrahepatic cholangiocarcinoma
• management
• risk factors
• staging
• targeted therapy

• Humans
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/therapy
• Bile Duct Neoplasms/genetics
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/therapy
• Cholangiocarcinoma/genetics
• Bile Ducts, Intrahepatic/pathology
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/complications
• Liver Neoplasms/diagnosis
• Liver Neoplasms/therapy
• Liver Neoplasms/complications

• Imaging feature
• Intrahepatic cholangiocarcinoma
• Meta-analysis
• Prognosis

• Humans
• Retrospective Studies
• Bile Duct Neoplasms/diagnostic imaging
• Bile Duct Neoplasms/surgery
• Cholangiocarcinoma/diagnostic imaging
• Cholangiocarcinoma/surgery
• Prognosis
• Magnetic Resonance Imaging
• Bile Ducts, Intrahepatic/diagnostic imaging
• Tomography, X-Ray Computed

• (31930020) Innovative Research Group Project of the National Natural Science Foundation of China
• (82102150) Innovative Research Group Project of the National Natural Science Foundation of China
• (BK20210968) Natural Science Foundation of Jiangsu Province
• ZDXYS202201 Jiangsu Science and Education Capacity Enhancement Project
• CXZX202203 Jiangsu Science and Education Capacity Enhancement Project
• Jiangsu Science and Education Capacity Enhancement Project

• antiangiogenic therapy
• chemotherapy
• conversion therapy
• immunotherapy
• intrahepatic cholangiocarcinoma

• Male
• Humans
• Middle Aged
• Gemcitabine
• Cisplatin/therapeutic use
• Bile Ducts, Intrahepatic/pathology
• Cholangiocarcinoma/pathology
• Deoxycytidine/therapeutic use
• Bile Duct Neoplasms/pathology

• National Natural Science Foundation of China

• Conversion therapy
• Intrahepatic cholangiocarcinoma
• Survival
• TACE
• lenvatinib

• National Cancer Database
• adjuvant therapy
• intrahepatic cholangiocarcinoma
• neoadjuvant therapy

• biomarkers
• surgical oncology

• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/pathology
• Bile Ducts, Intrahepatic/pathology
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/pathology
• Humans
• MicroRNAs/genetics
• Prognosis

• R01 CA202797 NCI NIH HHS
• R01 CA184792 NCI NIH HHS
• R01 CA181572 NCI NIH HHS
• R01 CA072851 NCI NIH HHS
• R01 CA227602 NCI NIH HHS
• Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)

We investigated lenvatinib plus programmed cell death-1 (PD-1) inhibitors as a first-line treatment for initially unresectable biliary tract cancer (BTC).

In this Phase II study, adults with initially unresectable BTC received lenvatinib (body weight ≥60 kg, 12 mg; <60 kg, 8 mg) daily and PD-1 inhibitors (pembrolizumab/tislelizumab/sintilimab/camrelizumab 200 mg or toripalimab 240 mg) every 3 weeks. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included surgical conversion rate, disease control rate (DCR), event-free survival (EFS), overall survival (OS) and tumor biomarkers.

Among 38 enrolled patients, the ORR was 42.1% and the DCR was 76.3%. Thirteen (34.2%) patients achieved downstaging and underwent surgery, six of whom (46.2%) achieved a major pathologic response (n=2) or partial pathologic response (n=4) in the primary tumor. In total, 84.2% of patients experienced ≥1 treatment-related adverse event (TRAE), 34.2% experienced a Grade ≥3 TRAE and no treatment-related deaths occurred. After a median follow-up of 13.7 months the median EFS was 8.0 months (95% CI: 4.6–11.4) and the median OS was 17.7 months (95% CI: not estimable).

Lenvatinib plus PD-1 inhibitors showed promising anti-tumor efficacy in patients with initially unresectable BTC and was generally well tolerated.

www.chictr.org.cn, ChiCTR2100044476.

• PD-1 inhibitors
• biliary tract cancer
• conversion surgery
• first-line treatment
• lenvatinib

Advanced intrahepatic cholangiocarcinoma (iCCA) is not suitable for surgical treatment. Guided by the concept of precision medicine, preoperative systematic treatment may reshape the clinical outcomes of advanced intrahepatic cholangiocarcinoma patients. We describe the case of a 38-year-old female who has been diagnosed with stage IV intrahepatic cholangiocarcinoma with a high tumor mutational burden and positively programmed death-ligand 1 (PD-L1) expression. The patient was treated with programmed cell death 1 (PD-1) inhibitors combined with tyrosine kinase inhibitors (TKIs). After 7 cycles of combination therapy, she underwent radical resection and no tumor cells were found in the postoperative histopathological examination. In addition, the patient’s survival time had reached 25 months, as of August 2021. To date, this is the first case of successful radical resection after combined immunotherapy with TKIs for advanced PD-L1-positive intrahepatic cholangiocarcinoma with a high tumor mutational burden (TMB). The case provides a new approach to the treatment of advanced intrahepatic cholangiocarcinoma.

• PD-L1
• TMB
• conversion therapy
• immunotherapy
• intrahepatic cholangiocarcinoma

Primary liver cancer has an insidious onset and no specific symptoms at early stage. Most patients are in the middle or advanced stage when diagnosed, and only 20%-40% of patients meet the criteria for radical resection. At present, surgical resection is still the main radical treatment for primary liver cancer, but factors such as liver function decompensation, too large tumor volume, too small future liver remnant, intrahepatic multiple metastasis, tumor thrombus invading the large vessels or bile duct, and distant metastasis limit the application of surgical resection or liver transplantation. In recent years, with the advances of basic research of primary liver cancer, the development of surgical techniques and equipment, as well as the development of new molecular targeted drugs and immunotherapy drugs, a part of unresectable patients with primary liver cancer can receive conversion therapy to improve liver function, minimize tumor volume, minimize or inactivate tumor thrombus, and increase the residual liver volume. Following conversion therapy, patients with primary liver cancer can undergo surgical resection or liver transplantation, which greatly improve the therapeutic efficacy and patient survival.

• Primary liver cancer
• Conversion therapy
• Indication
• Strategy

The first core tip of this study is that we summarized the experience of conversion therapy of intrahepatic cholangiocarcinoma (IHCC) in a single center and found conversion therapy could provide a significant improvement in the overall survival of patients with IHCC. Previous studies mainly focused on case reports and case series, and our research provided more evidence for the efficacy of conversion therapy in IHCC. The second is that we established the organoid of IHCC for drug screening and firstly verified the results of drug screening tests in cancer organoid were consistent with the levels of efficacy observed in the patient from whom it was derived. Cancer organoid is a promising technology for conversion therapy according to our study but more organoids are still needed.

This study was performed to determine the efficacy of conversion therapy in intrahepatic cholangiocarcinoma (IHCC) and explore the feasibility of cancer organoid to direct the conversion therapy of IHCC. Patient data were retrospectively reviewed in this study and cancer organoids were established using tissues obtained from two patients. A total of 42 patients with IHCC received conversion therapy, 9 of whom were downstaged successfully, and another 157 patients were initially resectable. Kaplan–Meier curves showed that the successfully downstaged patients had a significantly improved overall survival compared to those in whom downstaging was unsuccessful (p = 0.017), and had a similar overall survival to that of initially resectable patients (p = 0.965). The IHCC organoid was successfully established from one of two obtained tissues. Routine hematoxylin and eosin staining and immunohistological staining found the organoid retained the histopathological characteristics of the original tissues. Whole exome sequencing results indicated the IHCC organoid retained appropriately 87% of the variants in the original tissue. Gemcitabine and paclitaxel exhibited the strongest inhibitory effects on the cancer organoid as determined using drug screening tests, consistent with the levels of efficacy observed in the patient from whom it was derived. This study indicates that conversion therapy could improve the survival of patients with IHCC despite its low success rate, and it may be directed by cancer organoids though this is merely a proof of feasibility.

• conversion therapy
• drug screening
• genetic profiles
• intrahepatic cholangiocarcinoma
• organoid
• overall survival

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and is increasing in incidence. Long-term outcomes are optimized when patients undergo margin-negative resection followed by adjuvant chemotherapy. Unfortunately, a significant proportion of patients present with locally advanced, unresectable disease. Furthermore, recurrence rates are high even among patients who undergo surgical resection. The delivery of systemic and/or liver-directed therapies prior to surgery may increase the proportion of patients who are eligible for surgery and reduce recurrence rates by prioritizing early systemic therapy for this aggressive cancer. Nevertheless, the available evidence for neoadjuvant therapy in ICC is currently limited yet recent advances in liver directed therapies, chemotherapy regimens, and targeted therapies have generated increasing interest its role. In this article, we review the rationale for, current evidence for, and ongoing research efforts in the use of neoadjuvant therapy for ICC.

• Biliary tract cancer
• Preoperative therapy
• Conversion therapy
• Down-staging
• Hepatectomy
• Liver resection