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Background/aim: Gemcitabine (GEM)-based chemotherapy has been established as the core multimodal therapy for biliary tract cancer (BTC). However, the prognosis of BTC is unfavorable because of its resistance to GEM. Exosomes play important roles in the regulation of tumor progression and metastasis, immune dysregulation, and chemoresistance. This study investigated the effects of exosomes on GEM resistance in BTC., Materials and Methods: The human intrahepatic cholangiocarcinoma cell line CC-LP-1, its GEM-resistant (GR) derivative cell line CC-LP-1-GR, and the human intrahepatic cholangiocarcinoma cell lines HuCCA-1 and HuCCT1, were used. GEM resistance was examined by measuring cell viability in the presence of GEM using an MTS assay. Exosomes were isolated using ultracentrifugation and quantified using ELISA. Comprehensive expression analysis was performed using RNA sequencing. The effects of microRNAs were examined by miRNA mimic transfection., Results: The conditioned medium and exosomes derived from CC-LP-1-GR cells enhanced the GEM resistance of parental CC-LP-1 cells. In the presence of GEM, the p53 pathway was negatively enriched in CC-LP-1-GR and CC-LP-1 cells treated with exosomes from CC-LP-1-GR (rExo) compared to CC-LP-1 cells. The expression of miR-141-3p was higher in rExos than in CC-LP-1 cells. CC-LP-1 cells transfected with miR-141-3p mimic showed significantly (p<0.05) increased viability in the presence of GEM., Conclusion: A GEM-resistant human BTC cell line, CC-LP-1-GR, may acquire resistance to GEM by exosomes containing miR-141-3p., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. This pathway is being actively researched to assess its role in cancer immunotherapy., Patients and Methods: A total of 62 patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from March 2020 to August 2022 at Samsung Medical Center. DNACHK mutated were defined as genomic alterations, such as single nucleotide variants, multi-nucleotide variants, and short insertion and deletions in seven genes; checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair-associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, mediator of DNA damage checkpoint 1 (MDC1) and tumor protein p53 binding protein 1 (TP53BP1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs., Results: Patient median age at diagnosis was 68.0 years. 10 patients (16.1%) had GB cancer; the remaining patients (n=52, 83.9%) were diagnosed with cholangiocarcinoma. Thirty-seven (59.7%) patients were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). Patients in the DNACHK MT group had better disease control rate (DCR) than patients in the DNACHK WT (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI 5.1-22.8) in the MT group and 5.6 months (95%CI 3.1-11.0) in the WT group (p=0.33)., Conclusion: The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases., Materials and Methods: Bile was collected endoscopically or percutaneously from 52 patients with pancreatic cancer, 26 with biliary tract cancer, and 20 with benign pancreaticobiliary diseases. Sequences encoding 16 tumor-suppressive miRNAs were amplified by polymerase chain reaction and sequenced, and their methylation rates were determined., Results: The methylation rates of miR-1247 and miR-200a were significantly higher in patients with pancreatic cancer, and biliary tract cancer than in those with benign diseases, and the methylation rate of miR-200b was significantly higher in patients with pancreatic cancer than in those with benign diseases., Conclusion: Methylation of miR-1247, miR-200a, and miR-200b in bile may be useful for distinguishing PBC from benign diseases., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To elucidate the causes of cancer death in Japanese families with Lynch syndrome (LS)., Methods: The distributions of cancer deaths in 485 individuals from 67 families with LS (35, 30, and two families with MutL homologue 1 (MLH1), MSH2, and MSH6 gene mutations, respectively), obtained from the Registry of the Japanese Society for Cancer of the Colon and Rectum were analyzed., Results: Among 98 cancer deaths of first-degree relatives of unknown mutation status, 53%, 19%, 13% (among females), 7% (among females) and 5% were due to colorectal, gastric, uterine, ovarian, and hepatobiliary cancer, respectively. The proportion of deaths from extra-colonic cancer was significantly higher in families with MSH2 mutation than in those with MLH1 mutation (p=0.003)., Conclusion: In addition to colonic and uterine cancer, management and surveillance targeting gastric, ovarian and hepatobiliary cancer are considered important for Japanese families with LS. Extra-colonic cancer in families with MSH2 mutation might require for more intensive surveillance., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Polycomb repressive complex 2 (PRC2), an epigenetic master regulator, contributes to progression and development of biliary tract cancer (BTC). The present study investigated the effects of the PRC2 inhibitor 3-deazaneplanocin A (DZNep) on BTC cell lines., Materials and Methods: In vitro effects of DZNep treatment were analyzed for cell viability, gene expression and functional characteristics of cancer stem cell (CSC)., Results: DZNep treatment caused a cell line- and dose-dependent decrease in viability. In the EGI-1 cell line, a direct cytotoxic effect was accompanied by mRNA down-regulation of the PRC2 core components, cyclins as well as of CSC-related genes. Furthermore, DZNep affected putative CSCs by reduction of sphere formation and aldehyde dehydrogenase-1-positive cells. The stem cell characteristics of these subpopulations were verified by real-time polymerase chain reaction analysis., Conclusion: Taken together, our results show that DZNep might be a promising pharmacological agent for future therapies regarding BTC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: We analyzed the efficacy and toxicity profile of sunitinib according to single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor receptor (VEGFR) and Kinase insert domain receptor (KDR)., Patients and Methods: We examined eight known SNPs of VEGFA and five SNPs of KDR among patients with gastric or biliary tract cancer who were treated with sunitinib. We retrospectively assessed clinical outcomes and their relationships to these SNPs., Results: A total of 63 patients were evaluable. Among candidate SNPs, rs2010963 and rs833068 of VEGFA, and rs1870377 of KDR were associated with poor time to treatment failure (TTF) (p=0.009, 0.002, and 0.029, respectively), while rs1870377 and rs7692791 of KDR were associated with poor overal survival (OS) (p=0.001 and 0.03, respectively). Multivariate analysis showed that only rs1870377 had significant effects on both TTF and OS. Toxicity evaluation indicated that rs1531289 of KDR was associated with grade 3-4 anemia. (p=0.021)., Conclusion: Certain SNPs of KDR may affect treatment outcome and toxicity in patients treated with sunitinib.

Background/aim: Biliary tract carcinoma (BTC) has extremely poor prognosis because of rapid cancer cell proliferation. The aim of this study was to clarify the significance of keratinocyte growth factor receptor (KGFR) in the proliferation of BTC., Materials and Methods: The expression of KGFR in 34 surgical specimens of BTC was investigated by immunohistochemical staining. The effect of Ki23057, a small synthetic molecule that interrupts the autophosphorylation of KGFR, on the proliferation of human BTC cell lines was examined in vitro and in vivo., Results: The prognosis for BTC patients with KGFR-positive tumour was significantly poorer than that for those with KGFR-negative tumour. KGF significantly stimulated the proliferation of BTC cell lines. Ki23057 significantly decreased the growth of BTC cells in vitro and in vivo., Conclusion: KGFR may play an important role in the proliferation of BTC. KGFR phosphorylation inhibitor, Ki23057, therefore appears to be therapeutically promising in BTC.

Background: Biliary tract carcinoma (BTC) is a rare highly malignant neoplasia. Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing group-1 (ERCC1) and X-ray repair cross complementing group 1 (XRCC1) genes were evaluated and correlated with clinical outcome., Patients and Methods: Thirty-three patients with BTC were treated with intravenous or intra-arterial cisplatin and epirubicin and oral capecitabine. The ERCC1-C118T, XPD-Asp312Asn, XPD-Lys751Gln and XRCC1-Arg399Gln polymorphisms were studied., Results: A partial response (PR) occurred in 6 patients. The median progression-free (PFS) and overall survival (OS) were 4.8 and 18.9 months, respectively. No significant correlations were observed between response, PFS and OS in patients grouped according to all the studied polymorphisms. The analysis of survival starting from diagnosis resulted in a significant association of the XRCC1-Arg399Arg variant with a shorter survival., Conclusion: A role of the XRCC1-Arg399Gln polymorphism as a possible prognostic factor in patients affected by BTC is suggested.

Biliary tract cancer is of highly malignancy with a poor 5-year survival. However, established chemotherapeutic regimens have not yet been established. Previously, we have reported that hMLH1, a mismatch repair (MMR) gene was frequently (57%) found to be lacking in surgically resected biliary tract carcinomas and the patients lacking the expression of hMLH1 revealed a poorer prognosis than those patients who possessed it. The MMR gene has been considered to be associated with sensitivity to various chemotherapeutic agents that act on DNA. A loss of MMR expression has been reported to increase sensitivity to topoisomerase inhibitors such as etoposide (ETP) or camptothecins (CPT). In the present study, whether or not hMLH1 deficiency resulted in a higher sensitivity to irinotecan (CPT-11) active form (SN-38) was investigated using a short interfering (Si)RNA system. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) was conducted to measure the levels of hMLH1 expression in seven cancer cell lines, and this was compared with the drug sensitivity (IC50) to SN-38. The hMLH1 expression was correlated with the IC50 for SN-38, although the relationship was not statistically significant (R = 0.717, p = 0.0715). SiRNA double strand RNA (dsRNA) was transiently transfected into KMG-C (gallbladder cancer) cells. hMLH1 mRNA expression was repressed by hMLH1 dsRNA in a dose-dependent manner in comparison to the control dsRNA. The cell growth of the hMLH1 dsRNA transfected group was decreased by approximately 50% by SN-38 exposure. Flow cytometry was also carried out to examine the effect of the SN-38 treatment on the cell cycle. Following hMLH1 dsRNA transfection, the subG1 fraction was increased in comparison with the control in a dose-dependent manner. In conclusion, a low expression of hMLH1 in biliary tract cancer may aid in predicting its responsiveness to CPT-11 (SN38).

While pancreaticobiliary maljunctions (PBM) are clearly associated with biliary tract tumor development, little is known about their molecular mechanisms. This study was conducted to assess the contributions of microsatellite instability (MSI), mutations of transforming growth factor type II receptor (TGF-beta RII) and insulin-like growth factor type II receptor (IGF RII) genes and loss of heterozygosity (LOH) of hMSH2 and hMLH1 in 23 biliary tract tumors using PCR methods. MSI was detected by 13 markers in 16/23 samples (69.6%). TGF-beta RII mutations were detected in eight of these (50%), and of the IGF IIR gene in two (12.5%). LOH was detected in 4/16 (25%) at the hMSH2 locus, and 2/16 (12.5%) at the hMLH1 locus. No TGF-beta RII mutations or LOH of hMSH2 and hMLH1 were detected in MSI-negative samples. These findings suggest that MSI plays an important role in carcinogenesis of the biliary tract epithelium with PBM cases.