Usefulness of multigene liquid biopsy of bile for identifying driver genes of biliary duct cancers.

Liquid biopsy (LB) is an essential tool for obtaining tumor-derived materials with minimum invasion. Bile has been shown to contain much higher free nucleic acid levels than blood plasma and can be collected through endoscopic procedures. Therefore, bile possesses high potential as a source of tumor derived cell-free DNA (cfDNA) for bile duct cancers. In this study, we show that a multigene panel for plasma LB can also be applied to bile cfDNA for comparing driver gene mutation detection in other sources (plasma and tumor tissues of the corresponding patients). We collected cfDNA samples from the bile of 24 biliary tract cancer cases. These included 17 cholangiocarcinomas, three ampullary carcinoma, two pancreatic cancers, one intraductal papillary mucinous carcinoma, and one insulinoma. Seventeen plasma samples were obtained from the corresponding patients before surgical resection and subjected to the LiquidPlex multigene panel LB system. We applied a machine learning approach to classify possible tumor-derived variants among the prefiltered variant calls by a LiquidPlex analytical package with high fidelity. Among the 17 cholangiocarcinomas, we could detect cancer driver mutations in the bile of 10 cases using the LiquidPlex system. Of the biliary tract cancer cases examined with this method, 13 (54%) and 4 (17%) resulted in positive cancer driver mutation detection in the bile and plasma cfDNAs, respectively. These results suggest that bile is a more reliable source for LB than plasma for multigene panel analyses of biliary tract cancers.

Incidence of complications associated to bile duct stents, in patients with advanced cancer: a single-center experience.

BACKGROUND: Pancreatic cancer (PCa) and biliary tract carcinomas (BTCa) have high morbidity and mortality rates. Bile duct obstruction (BDO) develops in approximately 65-75% of PCa at diagnosis, delaying the administration of optimal treatment. In patients not candidates for surgery, BDO is usually treated through the endoscopy-guided placement of self-expanding stents in the bile duct. METHODS: In this retrospective study, we sought to describe clinical characteristics and outcomes of a cohort of patients with BDO of malignant origin who underwent biliary stent placement (BSP), with a special focus regarding complications developed after the procedure. Patients with PCa, BTCa, colon cancer, lung cancer, gastric cancer, and ovarian cancer who underwent BSP from 2014 to April 2019 at our institution were included in this cohort. Demographic and clinicopathologic characteristics were collected. Statistical analysis stratified according to ECOG performance status. Specific information regarding stent material (metallic vs. plastic), as well as incidence and type of complications derived from BSP, was also recorded. RESULTS: One hundred fifteen patients were included. The median age was 72 years. Sixty-six patients (57%) had PCa. All patients presented hyperbilirubinemia, which decreased after the procedure in 111 (96%) patients. Complications were observed in 44 (38%) patients, most of which 33 (75%) were infections. The median time to the complication was 1 month. The mean overall survival (OS) in our study was 20.3 weeks. CONCLUSION: BSP effectively decreased hyperbilirubinemia in patients with BDO; however, the procedure associated a significant rate of infectious complications, which can further compromise an effective anti-cancer therapy as well as optimal palliative strategies.

[Klatskin tumor - a case report]. / Guz Klatskina - opis przypadku.

UNLABELLED: Cholangiocarcinoma (CCA) is the second most frequent liver malignancy, responsible for 10-15% primary liver cancers. This tumor is difficult to diagnose and characterized by high mortality rate. Extrahepatic CCA is a specific type known as Klatskin tumor. A CASE REPORT: The patient was admitted to the Clinic of Internal Medicine and Gastroenterology with intrahepatic cholestasis. Imaging revealed Bismuth type IV hilum tumor. Due to rare occurrence of this malignancy the patient was directed to the tertiary center. During surgical exploration radical treatment was abandoned as a result of tumor's advanced stadium. Histology evaluation revealed infiltrating adenocarcinoma. ERCP and biliary duct stenting was performed. The patient was qualified for paliative chemotherapy according to gemcytabine+cisplatine protocol (d1, d15 every 28 days). Posttreatment follow-up revealed total remission of the tumor.

Immuno-genomic-radiomics to predict response of biliary tract cancer to camrelizumab plus GEMOX in a single-arm phase II trial.

Background & Aims: Immunotherapy is an option for the treatment of advanced biliary tract cancer (BTC), although it has a low response rate. In this post hoc analysis, we investigated the predictive value of an immuno-genomic-radiomics (IGR) analysis for patients with BTC treated with camrelizumab plus gemcitabine and oxaliplatin (GEMOX) therapy. Methods: Thirty-two patients with BTC treated with camrelizumab plus GEMOX were prospectively enrolled. The relationship between high-throughput computed tomography (CT) radiomics features with immuno-genomic expression was tested and scaled with a full correlation matrix analysis. Odds ratio (OR) of IGR expression for objective response to camrelizumab plus GEMOX was tested with logistic regression analysis. Association of IGR expression with progression-free survival (PFS) and overall survival (OS) was analysed with a Cox proportional hazard regression. Results: CT radiomics correlated with CD8+ T cells (r = -0.72-0.71, p = 0.004-0.047), tumour mutation burden (TMB) (r = 0.59, p = 0.039), and ARID1A mutation (r = -0.58-0.57, p = 0.020-0.034). There was no significant correlation between radiomics and programmed cell death protein ligand 1 expression (p >0.96). Among all IGR biomarkers, only four radiomics features were independent predictors of objective response (OR = 0.09-3.81; p = 0.011-0.044). Combining independent radiomics features into an objective response prediction model achieved an area under the curve of 0.869. In a Cox analysis, radiomics signature [hazard ratio (HR) = 6.90, p <0.001], ARID1A (HR = 3.31, p = 0.013), and blood TMB (HR = 1.13, p = 0.023) were independent predictors of PFS. Radiomics signature (HR = 6.58, p <0.001) and CD8+ T cells (HR = 0.22, p = 0.004) were independent predictors of OS. Prognostic models integrating these features achieved concordance indexes of 0.677 and 0.681 for PFS and OS, respectively. Conclusions: Radiomics could act as a non-invasive immuno-genomic surrogate of BTC, which could further aid in response prediction for patients with BTC treated with immunotherapy. However, multicenter and larger sample studies are required to validate these results. Impact and implications: Immunotherapy is an alternative for the treatment of advanced BTC, whereas tumour response is heterogeneous. In a post hoc analysis of the single-arm phase II clinical trial (NCT03486678), we found that CT radiomics features were associated with the tumour microenvironment and that IGR expression was a promising marker for tumour response and long-term survival. Clinical trial number: Post hoc analysis of NCT03486678.

[Intra and extra hepatic cholangiocarcinomas radiation therapy]. / Place de la radiothérapie des cholangiocarcinomes intra- et extrahépatiques.

Cholangiocarcinomas are digestive tumors whose incidence remains low and have poor prognosis. The benefits of adjuvant radiochemotherapy and radiotherapy have never been demonstrated in any phase III randomized controlled trial. Chemotherapy with capecitabine 6 months is the standard of care in adjuvant setting. Radiochemotherapy is validated in R1 patients. It is not recommended in neoadjuvant situations given the lack of evidence. Chemotherapy and radiochemotherapy are validated in adjuvant or locally advanced diseases. Stereotactic radiation therapy offers an interesting perspective, at the cost of significant digestive toxicities, requiring evaluation in randomized trials.

The Clinicopathological and Prognostic Value of PD-L1 Expression in Cholangiocarcinoma: A Meta-Analysis.

Background: Recently, blockade of immune checkpoint has emerged as one of the most potential treatments for solid tumors. Programmed cell death ligand 1(PD-L1), a member of the B7 family of molecules, plays a crucial role in tumor immunobiology. However, the prognostic significance of PD-L1 in cholangiocarcinoma (CCA) patients remains controversial. This study aimed to inquire into the prognostic and clinicopathological significance of PD-L1 in CCA via a meta-analysis. Methods: We searched PubMed, the Cochrane Library, Embase, Web of Science and Google Scholar up to April 2019, regardless of the region or language, for studies on the correlation between clinicopathology/prognosis and PD-L1 in patients with CCA. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the prognostic significance of PD-L1 expression in cholangiocarcinoma. The odds ratios (ORs) were also determined to explore the association between PD-L1 expression and clinicopathological features. Results: Our meta-analysis included 11 studies with 1,066 patients. The meta-analysis of these studies indicated a trend that high PD-L1 expression indicated a poor OS, but the result was not statistically significant (HR = 1.62, 95% CI [0.98-2.68], p = 0.063). For DFS, although the pooled result is not statistically significant, it trends toward being significant that high PD-L1 expression indicated improved DFS (HR = 0.80, 95% CI [0.62, 1.04], p = 0.092). In subgroup analyses, the results were not consistent across the subgroups that were divided based on the publication year (before 2018: HR = 1.92, 95% CI [1.34-2.75], p < 0.001; after 2018: HR = 1.42, 95% CI [0.70-2.89], p = 0.335). Moreover, PD-L1 expression in TCs significantly correlated with the AJCC TNM stage of CCA (OR = 0.52, 95% CI [0.27, 0.99], p = 0.09). Conclusion: Our meta-analyses revealed that PD-L1 expressed in TCs was significantly correlated with the AJCC TNM stage of CCA. Based on the included studies, we found that PD-L1 indeed expressed in both TCs and ICs in CCA patients, raising the possibility of the use of anti-PD-1/PD-L1 therapy for CCA patients. In contrast, expression of PD-L1 did not seem to be associated with patient outcome in our study. The prognostic role of PD-L1 in CCA demands further investigation.

Curative Resection After Gemcitabine, Cisplatin and S-1 Chemotherapy for Initially Unresectable Biliary Duct Cancer: A Case Report.

A 68-year-old woman was diagnosed with unresectable upper bile duct cancer with suspected invasion of the right hepatic artery and para-aortic lymph node metastasis (T4N3M0, stage IVb). She underwent plastic stent placement for obstructive jaundice and enrolled in our phase I study for unresectable biliary tract cancer consisting of cisplatin (25 mg/m(2) i.v. for 120 min) followed by gemcitabine (1,000 mg/m(2) i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days. After 8 courses of neoadjuvant chemotherapy without adverse effects, computed tomography showed near-complete disappearance of the tumor of the upper bile duct and of swollen lymph nodes. She then underwent sub-total stomach-preserving pancreatico duodenectomy and lymph node dissection. The pathological stage was pT1N0M0, stage I. The patient made a satisfactory recovery, was discharged 29 days after operation, and remains free of disease at 3 months after the operation under adjuvant chemotherapy using S-1.