Extrahepatic Cholangiocarcinoma Patients Research Articles

Retracted: Overexpression of 14-3-3δ Predicts Poor Prognosis in Extrahepatic Cholangiocarcinoma Patients.

[This retracts the article DOI: 10.1155/2020/8435420.].

Safety and efficacy of biliary stenting combined with iodine-125 seed strand followed by hepatic artery infusion chemotherapy plus lenvatinib with PD-1 inhibitor for the treatment of extrahepatic cholangiocarcinoma with malignant obstructive jaundice.

To evaluate the efficacy and safety of biliary stenting implantation with iodine-125 seed strand (SI) followed by hepatic artery infusion chemotherapy (HAIC) plus lenvatinib (Len) with programmed death-1 (PD-1) inhibitor for patients diagnosed with extrahepatic cholangiocarcinoma (ECC) and malignant obstructive jaundice (MOJ). In this single-center retrospective study, the data of ECC patients with MOJ from March 2015 to January 2023 was assessed. Using probability score matching (PSM), the selection bias of patients was reduced. Primary study outcomes included overall survival (OS) and progression-free survival (PFS). The OS and PFS were performed using the Kaplan-Meier method and evaluated with the log-rank test. A total of 104 patients were enrolled finally, including 52 patients treated with interventional therapy (SI+HAIC) plus Len with PD-1 inhibitor (SI+HAIC+Len+P group) and 52 patients treated with interventional therapy (SI+HAIC) plus lenvatinib (SI+HAIC+Len group). 26 pairs of patients were matched after PSM analysis. After PSM analysis, the median OS and PFS in the SI+HAIC+Len+P group were significantly longer compared to those in the SI+HAIC+Len group (OS:16.6 vs. 12.3 months, P = 0.001; PFS:12.6 vs 8.5 months, P = 0.004). The DCR was significantly different between groups (P = 0.039), while ORR not (P = 0.548). The addition of PD-1 inhibitor was generally well tolerated without treatment-associated mortality. Interventional therapy (SI+HAIC) plus Len with PD-1 inhibitor was effective for ECC patients accompanied by MOJ with a manageable safety profile.

PP443 Microbial dysbiosis in extrahepatic cholangiocarcinoma patients: A comparison of gut and mucosal microbiome with healthy controls

PP443 Microbial dysbiosis in extrahepatic cholangiocarcinoma patients: A comparison of gut and mucosal microbiome with healthy controls

Prognostic model for oversurvival and tumor-specific survival prediction in patients with advanced extrahepatic cholangiocarcinoma: a population-based analysis

BackgroundThe prognosis of patients with extrahepatic cholangiocarcinoma (ECCA) must be determined with precision. However, the usual TNM staging system has the drawback of ignoring age, adjuvant therapy, and gender and lacks the ability to more correctly predict patient prognosis. Therefore, we determine the risk factors of survival for patients with advanced ECCA patients and developed brand-new nomograms to forecast patients with advanced ECCA’s overall survival (OS) and cancer-specific survival (CSS).MethodFrom the Epidemiology and End Results (SEER) database, patients with advanced ECCA were chosen and randomly assigned in a ratio of 6:4 to the training and validation subgroups. The cumulative incidence function (CIF) difference between groups was confirmed by applying Gray’s and Fine test and competing risk analyses. Next, the cancer-specific survival (CSS) and overall survival (OS) nomograms for advanced ECCA were developed and validated.ResultsIn accordance with the selection criteria, 403 patients with advanced ECCA were acquired from the SEER database and then split at random into two groups: a training group (n = 241) and a validation group (n = 162). The 1-, 2-, and 3-year cancer-specific mortality rates were 58.7, 74.2, and 78.0%, respectively, while the matching mortality rates for the competition were 10.0, 13.8, and 15.0%. Nomograms were generated for estimating OS and CSS, and they were assessed using the ROC curve and the C-index. The calibration curves showed that there was a fair amount of agreement between the expected and actual probabilities of OS and CSS. Additionally, greater areas under the ROC curve were seen in the newly developed nomograms for OS and CSS when compared to the 7th AJCC staging system. The advanced ECCA patients were divided into groupings with an elevated risk and those with a low risk and the Kaplan-Meier method was used for the survival analysis, which showed that survival time was shorter in the high-risk group than in the low-risk group.ConclusionThe proposed nomograms have good predictive ability. The nomograms may can help doctors determine the prognosis of patients with advanced ECCA as well as provide more precise treatment plans for them.

MRI-based automatic identification and segmentation of extrahepatic cholangiocarcinoma using deep learning network

BackgroundAccurate identification of extrahepatic cholangiocarcinoma (ECC) from an image is challenging because of the small size and complex background structure. Therefore, considering the limitation of manual delineation, it’s necessary to develop automated identification and segmentation methods for ECC. The aim of this study was to develop a deep learning approach for automatic identification and segmentation of ECC using MRI.MethodsWe recruited 137 ECC patients from our hospital as the main dataset (C1) and an additional 40 patients from other hospitals as the external validation set (C2). All patients underwent axial T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and diffusion-weighted imaging (DWI). Manual delineations were performed and served as the ground truth. Next, we used 3D VB-Net to establish single-mode automatic identification and segmentation models based on T1WI (model 1), T2WI (model 2), and DWI (model 3) in the training cohort (80% of C1), and compared them with the combined model (model 4). Subsequently, the generalization capability of the best models was evaluated using the testing set (20% of C1) and the external validation set (C2). Finally, the performance of the developed models was further evaluated.ResultsModel 3 showed the best identification performance in the training, testing, and external validation cohorts with success rates of 0.980, 0.786, and 0.725, respectively. Furthermore, model 3 yielded an average Dice similarity coefficient (DSC) of 0.922, 0.495, and 0.466 to segment ECC automatically in the training, testing, and external validation cohorts, respectively.ConclusionThe DWI-based model performed better in automatically identifying and segmenting ECC compared to T1WI and T2WI, which may guide clinical decisions and help determine prognosis.

Immune checkpoint inhibitor-related molecular markers predict prognosis in extrahepatic cholangiocarcinoma.

Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications. Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI). Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36. TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.

Clinical Significance of Sphingosine 1-phosphate Receptor 2 and Takeda G Protein-coupled Receptor 5 in Extrahepatic Cholangiocarcinoma Patients.

In biliary epithelial cells, two bile acid receptors, sphingosine 1-phosphate receptor 2 (S1PR2) and Takeda G protein-coupled receptor 5 (TGR5) have been reported to trigger cell proliferation, as well as neoplastic cell invasiveness. In this study, we aimed to investigate the clinical significance of S1PR2/ TGR5 expression in extrahepatic cholangiocarcinoma (CCA) patients. Patients who underwent surgical resection of extrahepatic CCA at Korea University Guro Hospital between 2002 and 2018 were included. Data on immunohistochemical staining and H-score of S1PR2 and TGR5 were evaluated using digital image analysis. A total of 115 cases of invasive CCA were analyzed. The H-score of S1PR2 showed a decrease in invasive CCA (p=0.052) but that of TGR5 showed a significant increase (p=0.02). Overall survival and disease-free survival were significantly lower in the low S1PR2 expression group (p<0.05) than in the control group; however, TGR5 expression was not significant (p=0.096). In multivariate analysis, low S1PR2 was only significant for poor prognosis. Low S1PR2 level was the only independent poor prognostic factor in patients with resected extrahepatic CCA.

Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers.

BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a "genomic cohort" [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional "clinical cohort" of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT). In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.

Unraveling the heterogeneity of intercellular crosstalk in intrahepatic and extrahepatic cholangiocarcinoma using single-cell and spatial transcriptome profiling.

50 Background: Extrahepatic cholangiocarcinoma (ECC) and intrahepatic cholangiocarcinoma (ICC) are two types of malignant tumors that arise from the bile duct epithelium at different locations. Currently, effective treatment options for these tumors are limited, and their microenvironmental differences remain poorly understood. Methods: We collected retrospective clinicopathological data of ECC (N=64) and ICC (N=153) patients from our hospital and integrated public database information to analyze the clinical characteristics, survival, and prognosis of ECC and ICC. We performed single-cell sequencing (scRNA-seq) and spatial transcriptomic techniques on three ECC and three ICC tumor tissues. Verification of scRNA-seq results was done using immunohistochemistry, flow cytometry, and polychromatic immunofluorescence. Additionally, we analyzed RNA and ATAC sequencing data for exhausted CD8+ T cells TEX obtained from ICC and ECC tissue samples. We used InferCNV to infer copy number variations (CNVs) of epithelial cells from ICC and ECC. Results: Our results showed that ECC and ICC differ in their clinical characteristics such as age, gender, bilirubin, CEA, and outcome. ECC had higher copy number amplification variation and exhibited inflammatory signaling and ongoing immunoediting, reflected in higher immune checkpoint expression such as PDCD1, CTLA4, and LAG3, and tumor infiltration with highly differentiated dysfunctional PDCD1+ LAG3+ CXCL13+ exhausted CD8+ T cells (TEX) and precursors of exhausted T (TPEX). RNA velocity analysis revealed different developmental trajectories of T cells in ECC and ICC, predominantly in naive/stem-like and memory T cells. We also identified a trefoil factor 3 (TFF3)-positive epithelial subpopulation in ECC. TFF3+ epithelial cells had closer interaction with CTHRC1+ fibroblasts, which induced more CD8+ T cells to TEX and TPEX. TFF3+ cells exhibited higher CNV scores and higher PD-L1 and PD-L2 expression, and co-localized with TEX and TPEX, providing one explanation for the immunosuppressive environment in ECC and suggesting a potential response to immune checkpoint therapy (ICT). Conclusions: Our study provides a comprehensive characterization of the cellular heterogeneity landscape of ECC and ICC, which can guide the optimization of personalized cancer immunotherapy. We identified potential biomarkers and targets for immunotherapies, and our findings shed light on the underlying mechanisms of tumor immune evasion and provide a foundation for further research in this area.

Comparison of the tissue and gut microbiome in extrahepatic cholangiocarcinoma patients and healthy liver donors

Comparison of the tissue and gut microbiome in extrahepatic cholangiocarcinoma patients and healthy liver donors

Prognostic Value of Systemic Immune-Inflammation Index-Based Nomogram in Patients with Extrahepatic Cholangiocarcinoma Treated by Percutaneous Transhepatic Biliary Stenting Combined with 125I Seed Intracavitary Irradiation.

This study aimed to investigate the prognostic value of systemic immune-inflammation index (SII) in patients with extrahepatic cholangiocarcinoma (EHCC) treated by percutaneous transhepatic biliary stenting (PTBS) combined with 125I seed intracavitary irradiation and further develop a predictive model related to SII. A total of 145 patients with EHCC who received PTBS combined with 125I seed implantation were retrospectively analyzed. The optimal cut-off value of SII was identified by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curves and Cox regression were applied to estimate the prognostic value of SII and identify other significant factors of overall survival (OS). Additionally, a novel nomogram was constructed. The concordance index (C-index), calibration plots and decision curve analysis were used to evaluate the performance of the nomogram model. The optimal cut-off value for preoperative SII of 890.2 stratified the patients into High-SII (H-SII) and Low-SII (L-SII) groups. Univariate and multivariate analyses demonstrated that SII was an independent factor for OS. We also found that better therapeutic effect could be obtained with combined postoperative chemotherapy (P < 0.001). Moreover, we revealed that elevated preoperative CA19-9 (P = 0.038) and TBIL level (P = 0.024) were reason for poor prognosis of EHCC. A well-discriminated and calibrated nomogram was developed to predict the 1-year and 2-year OS of EHCC (C-index: 0.709). The SII may be a feasible and convenient prognosis predictor for EHCC. The comprehensive nomogram based on SII presented in this study is a promising model for predicting OS in EHCC patients after PTBS combined with 125I seed intracavitary irradiation.

Abstract 5903: Comparison of the tissue and gut microbiome in extrahepatic cholangiocarcinoma patients and healthy liver donors

Abstract Background: Biliary tract cancer (BTC) is an aggressive malignancy associated with a poor prognosis. Most BTC patients are diagnosed at an unresectable stage; further, the efficacy of cytotoxic chemotherapy for BTC remains unsatisfactory. Recently, there is growing evidence that gut microbial dysbiosis is related to multiple diseases, including biliary disease and cancer. However, the association between tumor and gut microbiome environments and BTC, especially extrahepatic cholangiocarcinoma (EH-CCA), remains unclear. In the present study, we compared the microbiome from the tissue and stool samples of EH-CCA patients and healthy living liver donors (controls). Methods: A total of 24 people (13 EH-CCA patients and 11 healthy controls) were included. We collected fecal and swab samples, which were obtained from the EH-CCA tissues of the patients and normal gallbladder tissues of the controls during operation. The bacterial 16S rRNA gene (V3 and V4 region) was amplified using PCR and sequenced on the Illumina MiSeq platform. The QIIME 2 pipelines were used to analyze the raw data. Results: The median age of the patients and controls were 70 (range, 58-79) and 29 (range, 19-35) years, respectively. The swab samples from EH-CCA patients showed significantly lower alpha diversity than the samples from the controls (pShannon &amp;lt; 0.001). Proteobacteria was the most commonly found phylum (53%) in the EH-CCA patients; Firmicutes (79%) and Actinobacteria (13%) were the common phyla in the controls. The genera Streptococcus (25.1%), Escherichia_Shigella (16.9%), and Enterococcus (13.9%) were found in the patient samples, whereas Blautia (12%), Limosilactobacillus (12%), and Bifidobacterium (19%) were observed in the controls. The Principal Coordinate Analysis (PCoA) plot of the weighted UniFrac distances showed that the patient and control groups formed separate clusters. Among the fecal samples, Streptococcus (12.5%), bacterioides (8.2%) is most common in patients’ group, whereas Blautia (13.8%) and Faecalibacterium (11.5%) is most common in control group at the gene levels. The PCoA plot of the fecal samples showed significant differences in microbiota composition between the EH-CCA patients and healthy controls (P=0.001 by PERMANOVA). In the beta diversity analysis of all samples (swab plus fecal), the patient-swab samples formed distinct clusters, whereas the patient-fecal, control-swab, and control-fecal samples showed overlapping clusters.Conclusions: To the best of our knowledge, this study is the first that compares the microbiome of tissues and stools from EH-CCA patients and healthy controls; the EH-CCA patients and healthy controls showed different microbiota profiles. Further studies are needed to investigate the clinical implications of microbial dysbiosis in BTC and formulate novel microbiome-based treatments for BTC. Citation Format: Sora Kang, Jihee Kang, Gun-Seok Park, Seung-Hyun Ko, Jung-Hyun Park, Yunseon Jang, Ik-Chan Song, Hyewon Ryu, Seok-Hwan Kim. Comparison of the tissue and gut microbiome in extrahepatic cholangiocarcinoma patients and healthy liver donors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5903.

Photodynamic therapy combined with systemic chemotherapy for unresectable extrahepatic cholangiocarcinoma: A systematic review and meta-analysis.

Extrahepatic cholangiocarcinoma (ECC) is a tumor with high invasiveness and poor outcome. The current treatments for unresected ECC are not ideal. Novel strategies are needed to improve the outcomes of patients with unresected ECC. Photodynamic therapy (PDT) plus chemotherapy is one of the promising interventions for ECC patients. We conducted this systematic review to determine the efficacy and safety of PDT plus chemotherapy in unresected ECC patients. Databases of PubMed, Cochrane Library, Embase, and Web of science were searched from inception to July 2022. Studies that compared PDT plus chemotherapy to PDT alone or chemotherapy alone in patients with unresected ECC were included. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled for overall survival (OS) and adverse events, respectively. Seven eligible studies were finally included. There are four studies on PDT plus chemotherapy vs. chemotherapy alone and three studies on PDT plus chemotherapy vs. PDT alone. The meta-analysis showed that PDT plus chemotherapy had a significantly better OS than chemotherapy or PDT alone (PDT+chemotherapy vs. chemotherapy alone, HR: 0.69, p=0.02; PDT+chemotherapy vs. PDT alone, HR:0.36, p<0.01). The occurrence of cholangitis, abscess, and photosensitivity reaction in PDT plus chemotherapy were comparable to either chemotherapy alone or PDT alone (p>0.05). The combination of PDT and chemotherapy can improve patient survival for unresected ECC without increased adverse events. It may be a potential standard therapy in the future management of ECC.

Establishment and validation of a prognostic nomogram for extrahepatic cholangiocarcinoma.

Accurately estimate the prognosis of patients with ECCA is important. However, the TNM system has some limitations, such as low accuracy, exclusion of other factors (e.g., age and sex), and poor performance in predicting individual survival risk. In contrast, a nomogram-based clinical model related to a comprehensive analysis of all risk factors is intuitive and straightforward, facilitating the probabilistic analysis of tumor-related risk factors. Simultaneously, a nomogram can also effectively drive personalized medicine and facilitate clinicians for prognosis prediction. Therefore, we construct a novel practical nomogram and risk stratification system to predict CSS in patients with ECCA. Accurately estimate the prognosis of patients with extrahepatic cholangiocarcinoma (ECCA) was important, but the existing staging system has limitations. The present study aimed to construct a novel practical nomogram and risk stratification system to predict cancer-specific survival (CSS) in ECCA patients. 3415 patients diagnosed with ECCA between 2010 and 2015 were selected from the SEER database and randomized into a training cohort and a validation cohort at 7:3. The nomogram was identified and calibrated using the C-index, receiver operating characteristic curve (ROC), and calibration plots. Decision curve analysis (DCA), net reclassification index (NRI), integrated discrimination improvement (IDI) and the risk stratification were used to compare the nomogram with the AJCC staging system. Nine variables were selected to establish the nomogram. The C-index (training cohort:0.785; validation cohort:0.776) and time-dependent AUC (>0.7) showed satisfactory discrimination. The calibration plots also revealed that the nomogram was consistent with the actual observations. The NRI (training cohort: 1-, 2-, and 3-year CSS:0.27, 0.27,0.52; validation cohort:1-,2-,3-year CSS:0.48,0.13,0.34), IDI (training cohort: 1-, 2-, 3-year CSS:0.22,0.18,0.16; validation cohort: 1-,2-,3-year CSS:0.18,0.16,0.17), and DCA indicated that the established nomogram significantly outperformed the AJCC staging system (P<0.05) and had better recognition compared to the AJCC staging system. We developed a practical prognostic nomogram to help clinicians assess the prognosis of patients with ECCA.

Preoperative peripheral blood inflammatory markers especially the fibrinogen-to-lymphocyte ratio and novel FLR-N score predict the prognosis of patients with early-stage resectable extrahepatic cholangiocarcinoma.

Systemic inflammation is important in the development of extrahepatic cholangiocarcinoma (ECC). The aim of this study was to compare the prognostic power of preoperative peripheral blood inflammatory markers and the novel FLR-N score in patients with resectable ECC. A total of 140 patients with resectable ECC and 140 healthy controls (HCs) were recruited for the study. The Mann-Whitney U test was used to evaluate the differences in inflammatory markers between groups. Kaplan-Meier and Cox regression analyses were used to evaluate the prognostic power of preoperative fibrinogen, albumin, prealbumin, bilirubin, neutrophils, lymphocytes, monocytes, platelets, fibrinogen-to-lymphocyte ratio (FLR), fibrinogen-to-albumin ratio (FAR), fibrinogen-to-prealbumin ratio (FPR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), FLR-neutrophil (FLR-N) score, and CA19-9 in patients with resectable ECC. Nomogram was developed based on the results of multivariate Cox analyses. Patients with resectable ECC had significantly higher levels of neutrophils, monocytes, fibrinogen, FLR, FAR, FPR, NLR, PLR, and MLR and lower levels of lymphocytes, albumin, and prealbumin than HCs (all P < 0.01). Albumin, prealbumin, and FPR had a good ability to distinguish between ECC patients with total bilirubin < 34 µmol/L and HCs (AUCs of 0.820, 0.827, and 0.836, respectively). Kaplan-Meier analysis showed that high neutrophil, fibrinogen, FLR, FAR, PLR, MLR, and FLR-N score values were associated with poor survival in patients with resectable ECC. Multivariate analyses indicated that neutrophils (P = 0.022), FLR (P = 0.040), FLR-N score (P < 0.0001), and positive lymph node metastasis (P = 0.016) were independent factors for overall survival (OS). Nomogram were developed to predict OS for patients with ECC. The prognostic roles of inflammatory markers in patients with resectable ECC were different. The preoperative neutrophil count, FLR and FLR-N score could serve as noninvasive markers for predicting the prognosis of resectable ECC.

Impact of lncRNA SOX9-AS1 overexpression on the prognosis and progression of intrahepatic cholangiocarcinoma

BackgroundIntrahepatic cholangiocarcinoma (ICC) is a latent and malignant tumor with a dismal prognosis. This study was to evaluate the clinical relevance and therapeutic potential of SOX9-AS1 expression in ICC. MethodsThe cancerous tissues and adjacent normal tissues were collected from ICC patients. Blood samples from ICC, hepatocellular carcinoma (HCC) group, the extrahepatic cholangiocarcinoma (ECC) group and the healthy controls were collected. SOX9-AS1 levels were evaluated in tissues (versus normal tissues) and plasma samples (versus plasma from HCC and ECC by quantitative real-time RT-PCR. The diagnostic value of SOX9-AS1 for ICC was estimated using receiver operating characteristic (ROC) curves. The relevancy between SOX9-AS1 expression and overall survival or recurrence-free survival was assessed by Kaplan-Meier curves multivariate analyses. The overexpression and knockdown of SOX9-AS1 on cell behavior were assessed by CCK-8 and transwell assay. ResultsSOX9-AS1 levels were increased in ICC, both in the tissues and the cell lines. The upregulation of SOX9-AS1 showed a highly discriminative profile, distinguishing ICC patients from healthy subjects or HCC or ECC patients. Upregulation of SOX9-AS1 was related to shorter overall survival and recurrence-free survival. Muli-variate analysis revealed that SOX9-AS1 expression was an independent prognostic purpose factor of worst overall survival and recurrence-free survival. ConclusionsSOX9-AS1 drives tumor growth and metastasis in ICC. SOX9-AS1 may be applied as a new diagnostic and prognostic purposed marker, in addition to a promising therapeutic target in ICC.

Single-cell landscape of immunocytes in patients with extrahepatic cholangiocarcinoma

BackgroundThe intricate landscape of immunocytes in the tumor microenvironment (TME) is fundamental to immunotherapy but notably under-researched in extrahepatic cholangiocarcinoma (ECCA).MethodsSingle-cell RNA sequencing technology was conducted to make an in-depth analysis of immunocytes from matched tumor tissues, paratumor tissues and peripheral blood from ECCA patients. The potential cellular interactions between two cell populations were analyzed with software CellPhoneDB (v2.1.7).ResultsWe obtained 13526 cells and characterized the transcriptomes and heterogeneity of different clusters and subclusters of immunocytes from ECCA, including CD4+ T cells, CD8+ T cells, B cells and myeloid immunocytes. We observed the rarely described immunocyte subclusters "intermediate" exhausted CD8+ T (CD8+ Tex) cells and “nonclassic” plasmacytes (CD27+ CD138+ CD38−). In addition, we identified potential immunotherapy targets, for example, ACP5, MAGEH1, TNFRSF9 and CCR8 for Tregs and MT1 for CD8+ Tex cells. We also found strong cellular interactions among Treg cells, M2 macrophages and CD8+ Tex cells through ligand–receptor analysis, implying that potential cellular cross-linkage promoted the immunosuppressive nature of the TME.ConclusionsIn a word, our study illuminated the components of the TME and revealed potential cellular interactions at the individual cellular level in ECCA, we aimed to provide a new perspective for further immunological studies and immunotherapy of ECCA.

The association of family history of primary liver cancer with cholangiocarcinoma: USA case-control study.

403 Background: The incidence of cholangiocarcinoma (CCA), particularly intrahepatic cholangiocarcinoma (IHC) has exponentially increased in the United States since 2007. While cholangiocarcinomas share some common characteristics, increasing evidence suggests that different subtypes of CCA have divergent tumor microenvironments, pathobiology and distinct epidemiologic features and risk factors. The correlation between family history of cancer and cholangiocarcinoma remains to be determined. This study aims to address the connection between positive family history of primary liver cancer and development of cholangiocarcinoma, including intrahepatic cholangiocarcinoma (IHC) and extrahepatic cholangiocarcinoma (EHC), in USA. Methods: At The University of Texas M. D. Anderson Cancer Center, we studied 429 patients with pathologically confirmed cholangiocarcinoma (308 IHC, 121 EHC) and 1,075 healthy controls. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the subjects’ relationship with the relative, and the age at which the relative was diagnosed. Results: Independent of hepatitis B virus (HBV) and hepatitis C virus (HCV), a family history of cancer was significantly associated with IHC and EHC, the estimated ORs and 95% CI were 1.6 (1.2-2.2) and 1.6 (1.1-2.5) for IHC and EHC respectively. Primary liver cancer in first-degree relatives was significantly associated with EHC development (OR 9.4 [95% CI, 2.9-30.7]). No significant association was observed for IHC, (OR 1.7 [95% CI, 0.5-5.9]). The prevalence of family history of primary liver cancer in first-degree members was recorded in 6.6% of EHC patients and in 1.6% of IHC patients. Multiple relatives with primary liver cancer were observed in 5 patients (4.1%) among EHC subjects but less common in IHC (1%). All estimated ORs were adjusted for age, sex, race, smoking, alcohol, Hepatitis virus infection, diabetes, and obesity. Conclusions: First-degree family history of primary liver cancer is associated with EHC development in USA independent of known risk factors for CCA. Further research exploring the genetic–environment interactions associated with EHC is warranted. Focused efforts in identifying the population at increased risk for developing EHC are necessary and may lead to new screening and surveillance strategies.

Metformin Use and Survival in Patients with Advanced Extrahepatic Cholangiocarcinoma: A Single-Center Cohort Study in Fuyang, China.

Aims Metformin is an oral antidiabetic agent that has been widely prescribed for the treatment of type II diabetes. In recent years, anticancer properties of metformin have been revealed for numerous human malignancies. However, there are few indications available regarding the feasibility and safety of these studies in an advanced extrahepatic cholangiocarcinoma (EHCC) population. This study is aimed at evaluating the feasibility, safety, and value of metformin use and survival in patients with advanced EHCC. Methods All patients with advanced EHCC observed at Fuyang People's Hospital between January 2015 and November 2020 were included in the study. Case data, clinical information, and imaging results were abstracted from the self-administered questionnaire and electronic medical record. All patients were divided into study subjects and control subjects, and the study subjects were given metformin, 0.5 g, three times a day, while control subjects were without metformin. The metformin use and survival time of the subjects were asked by telephone, out-patient, or door-to-door visit, after they left the hospital. Results One hundred and thirty-three study cases and 589 controls were included in the analysis. This study showed that metformin use cannot improve the overall survival rate of patients with advanced EHCC ([95% CI]: -17.05-0.375, t = −1.889, P value = 0.061), but the survival time of patients with drainage treatment from control group (n = 496) was significantly shorter than that of patients with drainage treatment from the study group (n = 113), and the difference was statistically significant (z = −2.230, P value = 0.026). There were significant differences between metformin used before or after the diagnosis of advanced EHCC (OR[95% CI], 3.432[2.617-4.502]; P value = 0.001) in survival time. And there was significant difference between the duration of metformin use and survival prognosis (OR[95% CI], 2.967[1.383-6.368]; P = 0.005). Conclusion Metformin can improve the survival of advanced EHCC patients who underwent drainage treatment, especially for metformin use after diagnosis of advanced EHCC and long duration of metformin.

Inpatient Palliative Care Is Less Utilized in Rare, Fatal Extrahepatic Cholangiocarcinoma: A Ten-Year National Perspective.

Background—Extrahepatic cholangiocarcinoma (ECC) is a rare, morbid, fatal cancer with distressing symptoms. Maintaining a high quality of life while reducing hospital charges and length of stay (LOS) for the end-of-life period remains a major challenge for the healthcare system. Palliative care utilization has been shown to address these challenges; moreover, its use has increased in recent years among cancer patients. However, the utilization of palliative care in rare cancers, such as ECC, has not yet been explored. Objectives—To investigate palliative care utilization among ECC patients admitted to US hospitals between 2007 and 2016 and its association with patient demographics, clinical characteristics, hospital charges, and LOS. Methods—De-identified patient data of each hospitalization were retrieved from the National Inpatient Sample (NIS) database. Codes V66.7 (ICD-9-CM) or Z51.5 (ICD-10-CM) were used to find palliative care utilization. Multivariate adjusted logistic regression analyses were conducted to assess factors associated with palliative care use, LOS, hospital charges, and in-hospital death. Results—Of 4426 hospitalizations, only 6.7% received palliative care services. Palliative care utilization did not significantly increase over time (p = 0.06); it reduced hospital charges by USD 25,937 (p < 0.0001) and LOS by 1.3 days (p = 0.0004) per hospitalization. Palliative care was positively associated with female gender, severe disease, and age group ≥80 (p ≤ 0.05). The average LOS was 8.5 days for each admission. Conclusions—Hospital admissions with palliative care utilization had lower hospital charges and LOS in ECC. However, ECC patients received less palliative care compared with more common cancers sharing similar symptoms (e.g., pancreatic cancer). ECC patients also had longer LOS compared with the national average. Further research is warranted to develop interventions to increase palliative care utilization among ECC hospital patients.