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1.
Langenbecks Arch Surg ; 408(1): 58, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688973

RESUMO

PURPOSE: This study aimed to elucidate the safety and oncological outcomes of surgery with hepatic artery resection (HAR) for patients with distal cholangiocarcinoma. METHODS: The clinical data of patients with distal cholangiocarcinoma who underwent curative intent surgery at Hiroshima University between March 2009 and January 2021 were retrospectively analyzed. Eligible patients were classified according to the presence or absence of HAR (HAR and non-HAR group), and clinicopathological features and disease-free survival rates were compared between the two groups. RESULTS: Among the 60 patients analyzed, eight patients had received HAR, and the remaining 52 patients had not. The rate of portal vein resection, T stage, and the number of metastasized lymph nodes in the HAR group were significantly greater than those in the non-HAR group (p < 0.001, p = 0.00695, and p = 0.0480, respectively). Postoperative severe complication was confirmed in one patient, and there were no in-hospital deaths in the HAR group. Seven of 8 patients in the HAR group showed recurrence during follow-up, and of those, six patients showed early recurrence within 1 year postoperatively. The disease-free survival time in the HAR group was significantly shorter than that in the non-HAR group (median: 7.4 m vs. 34.2 m, respectively) (p < 0.001). Multivariate analysis revealed that lymph node metastasis and HAR were significant risk factors for predicting the adverse disease-free survival time (hazard ratio (HR), 3.21; p = 0.0142; HR, 4.47; p = 0.0346, respectively). CONCLUSIONS: Patients with distal cholangiocarcinoma who underwent surgery with HAR tended to show early recurrences, although HAR could be performed safely.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Artéria Hepática , Humanos , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Colangiocarcinoma/cirurgia , Hepatectomia , Artéria Hepática/cirurgia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
2.
Curr Oncol ; 30(1): 1032-1045, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36661728

RESUMO

BACKGROUND: Unresectable cholangiocarcinoma prognosis can be extremely variable due to different symptoms and sites of disease involvement at diagnosis and unpredictable chemotherapy response rates. Most patients will usually receive 1st line palliative chemotherapy with platinum compounds and Gemcitabine or Gemcitabine alone. Only a few patients maintain adequate performance status after first-line treatment failure: second-line treatment with FOLFOX or FOLFIRI chemotherapy has been used in this setting with modest overall survival improvement. There is a lack of data concerning whether laboratory findings might help clinicians in identifying those patients with the highest likelihood of benefiting from 2nd line treatment. The aim of this analysis is to assess the prognostic role of a series of easily available laboratory tests in patients with bile duct cancer who received 2nd line chemotherapy. PATIENTS AND METHODS: Patients with unresectable bile duct cancer treated in 2nd-line setting with platinum-based chemotherapy doublet or FOLFIRI were enrolled. The primary objective of the analysis was to assess overall survival (OS) differences among patients based on the results of lab tests. Serum hemoglobin, neutrophil, lymphocyte, monocyte, platelet absolute count, creatinine, total bilirubin, albumin, LDH, circulating CEA and CA19.9 values were collected at the start of 2nd line treatment. Cut-off values for all lab tests were set by ROC curve analysis. Survival was calculated by the Kaplan-Meier method and differences in survival among stratification factors were assessed by Log-rank test. Cox-proportional-hazard regression was used for multivariate analysis. Level of statistical significance p was set at 0.05 for all tests. Correction for false discovery error rate was performed by Holm's stepdown procedure. RESULTS: A total of 46 patients were eligible. Median overall survival of the entire cohort was 8.98 months (95%CI: 6.68-13.93) while mean OS was 17.10 months (standard error: 3.16). Using 6.2 months OS landmark as classification variable for ROC curve analysis, only serum hemoglobin (cut-off: >10 g/dL), albumin (cut-off: >3.5 mg/dL), CA19.9 (cut-off: ≤668 UI/mL), monocyte (cut-off: ≤510/mmc) and neutrophil count (cut-off: ≤5140/mmc) were significantly associated with the chosen end-point. Multivariate analysis confirmed an independent statistically significant impact on overall survival only for hemoglobin (Exp(b): 0.12, p = 0.0023) and neutrophil count (Exp(b): 0.30, p = 0.0039). Based on these results, using both hemoglobin and neutrophil count, three prognostic groups were defined: patients with both favorable factors had 12.63 months median OS vs. 6.75 months of patients with only one favorable factor vs. 1.31 months of those with neither. The difference between these three groups of patients was statistically significant (p < 0.0001). DISCUSSION: Second-line palliative chemotherapy can be a potentially useful option for a few patients with unresectable/metastatic bile duct cancer. Even though assessment of patients' prognosis might be difficult due to the complex behavior of this disease, a series of easily available laboratory tests might be used for these means: serum hemoglobin and neutrophil count we0re able to define subsets of patients with entirely different prognoses. It is hoped that this score will be prospectively validated in a larger group of patients in order to improve treatment decisions in patients with unresectable bile duct cancer candidate to receive palliative 2nd line chemotherapy.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Prognóstico , Neutrófilos/patologia , Estudos Retrospectivos , Albuminas , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Hemoglobinas
3.
In Vivo ; 37(1): 294-303, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593058

RESUMO

BACKGROUND/AIM: Recently, we reported that coiled-coil domain containing 25 (CCDC25) protein is elevated in the sera of patients with cholangiocarcinoma (CCA) and is suggested to be a diagnostic biomarker for CCA. This study aimed to examine whether serum CCDC25 level can be a unique biomarker for CCA. Bioinformatic analyses using Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) indicated that CCDC25 protein and mRNA are expressed not only in CCA but also in other cancers, such as colorectal cancer (CRC), breast cancer (BC), and hepatocellular carcinoma (HCC), all of which are the top 5 cancers highly prevalent in Thailand. MATERIALS AND METHODS: Using a quantitative dot blot assay, serum CCDC25 levels were measured for 30 healthy controls (HC), 34 CRC, 42 BC, 43 HCC, and 83 CCA. RESULTS: The serum CCDC25 levels of CCA patients (0.193±0.039 ng/µl) were significantly higher than those of CRC (0.019±0.006 ng/µl), BC (0.036±0.015 ng/µl), HCC (0.035±0.016 ng/µl), and higher than those of HC (0.012±0.003 ng/µl). The serum CCDC25 level can discriminate CCA from the HC, CRC, BC, and HCC with a sensitivity of 100, 99, 94, and 94%, respectively, and specificity of 100, 100, 98, and 95%, respectively. CONCLUSION: CCDC25 is a candidate diagnostic biomarker for CCA.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Ductos Biliares Intra-Hepáticos/metabolismo , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia
4.
Medicina (Kaunas) ; 59(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36676763

RESUMO

Background and Objectives: Rho GTPase-activating protein (RhoGAP) is a negative regulatory element of Rho GTPases and participates in tumorigenesis. Rho GTPase-activating protein 21 (ARHGAP21) is one of the RhoGAPs and its role in cholangiocarcinoma (CCA) has never been disclosed in any publications. Materials and Methods: The bioinformatics public datasets were utilized to investigate the expression patterns and mutations of ARHGAP21 as well as its prognostic significance in CCA. The biological functions of ARHGAP21 in CCA cells (RBE and Hccc9810 cell) were evaluated by scratch assay, cell counting kit-8 assay (CCK8) assay, and transwell migration assay. In addition, the underlying mechanism of ARHGAP21 involved in CCA was investigated by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the most significant signaling pathway was identified through gene set enrichment analysis (GSEA) and the Western blot method. The ssGSEA algorithm was further used to explore the immune-related mechanism of ARHGAP21 in CCA. Results: The ARHGAP21 expression in CCA tissue was higher than it was in normal tissue, and missense mutation was the main alteration of ARHGAP21 in CCA. Moreover, the expression of ARHGAP21 had obvious differences in patients with different clinical characteristics and it had great prognostic significance. Based on cell experiments, we further observed that the proliferation ability and migration ability of the ARHGAP21-knockdown group was reduced in CCA cells. Several pathological signaling pathways correlated with proliferation and migration were determined by GO and KEGG analysis. Furthermore, the PI3K/Akt signaling pathway was the most significant one. GSEA analysis further verified that ARHGAP21 was highly enriched in PI3K/Akt signaling pathway, and the results of Western blot suggested that the phosphorylated PI3K and Akt were decreased in the ARHGAP21-knockdown group. The drug susceptibility of the PI3K/Akt signaling pathway targeted drugs were positively correlated with ARHGAP21 expression. Moreover, we also discovered that ARHGAP21 was correlated with neutrophil, pDC, and mast cell infiltration as well as immune-related genes in CCA. Conclusions: ARHGAP21 could promote the proliferation and migration of CCA cells by activating the PI3K/Akt signaling pathway, and ARHGAP21 may participate in the immune modulating function of the tumor microenvironment.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Biologia Computacional , Ductos Biliares Intra-Hepáticos , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Proliferação de Células/genética , Movimento Celular/genética , Microambiente Tumoral , Proteínas Ativadoras de GTPase/genética
5.
Clin Epigenetics ; 15(1): 13, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694230

RESUMO

BACKGROUND: Collagen type XII alpha 1 chain (COL12A1) is associated with human cancer progression. Nevertheless, the expression pattern and the function of COL12A1 in intrahepatic cholangiocarcinoma (iCCA) remain unknown. The present study was performed to assess the role of COL12A1 in iCCA. RESULTS: A total of 1669 genes, differentially expressed between iCCA and nontumor liver tissue samples, were identified as potential tumor-specific biomarkers for iCCA patients. Of these, COL12A1 was significantly upregulated in clinical iCCA tissue samples and correlated with epithelial-mesenchymal transition gene set enrichment score and advanced tumor stage in clinical iCCA. COL12A1-high expression was associated with the poor prognoses of iCCA patients (n = 421) from four independent cohorts. Promoter hypermethylation-induced downregulation of miR-424-5p resulted in COL12A1 upregulation in clinical iCCA. Experimental knockout of COL12A1 inhibited the proliferation, invasiveness and growth of iCCA cells. MiR-424-5p had a therapeutic potential in iCCA via directly targeting COL12A1. CONCLUSIONS: Promoter hypermethylation-induced miR-424-5p downregulation contributes to COL12A1 upregulation in iCCA. COL12A1 is a promising druggable target for epigenetic therapy of iCCA.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , MicroRNAs , Humanos , Regulação para Cima , Neoplasias dos Ductos Biliares/genética , Metilação de DNA , Colangiocarcinoma/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Epigênese Genética , MicroRNAs/genética , MicroRNAs/metabolismo , Colágeno Tipo XII/genética , Colágeno Tipo XII/metabolismo
6.
Anticancer Res ; 43(2): 645-652, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36697100

RESUMO

BACKGROUND/AIM: This study evaluated the clinical implications of epithelial-mesenchymal transition (EMT) markers and peritumoral immune cell infiltration in patients with biliary tract cancer (BTC) treated with gemcitabine plus cisplatin (GemCis). MATERIALS AND METHODS: Forty-five patients with advanced BTC who received GemCis were included as the study population. We conducted multiplex immunohistochemistry and examined EMT markers and their correlations with immune cell infiltrate at the invasive tumor margin. Study population was subdivided into two groups: twenty-four patients with overall survival (OS) less than 10 months (short-term survivor group, SS) and 21 with OS of 20 months or longer (long-term survivor group, LS). RESULTS: The density of tumor cells expressing epithelial marker E-cadherin (E-cadherin+ CK+) at the invasive tumor margin tended to be higher in the LS group than that in the SS group (p=0.065). The density of tumor cells expressing mesenchymal marker vimentin (vimentin+ CK+) was significantly higher in the SS group than that in the LS group (p=0.021). The density of E-cadherin- vimentin+ tumor cells (E-cadherin- vimentin+ CK+) was also significantly higher in the SS group (p=0.020). The density of OX40 expressing cells was significantly higher in the SS group compared to that in the LS group (p=0.006). The density of vimentin-expressing tumor cells was positively correlated with FoxP3+ CD4+ regulatory T-cells (r=0.29, p=0.047) and OX40+ cells (r=0.48, p<0.001). CONCLUSION: EMT-related features were enriched in BTC patients with poor survival outcomes and associated with regulatory T-cell infiltration.


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Humanos , Transição Epitelial-Mesenquimal/genética , Vimentina/genética , Caderinas/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Desoxicitidina/uso terapêutico , Fenótipo , Biomarcadores Tumorais
7.
N Engl J Med ; 388(3): 228-239, 2023 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-36652354

RESUMO

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).


Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma , Inibidores de Proteínas Quinases , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Idoso , Humanos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de Vida , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Antineoplásicos/administração & dosagem
8.
Clinics (Sao Paulo) ; 78: 100163, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36681067

RESUMO

Biliary drainage for Perihilar Cholangiocarcinoma (PCCA) can be performed either by endoscopic retrograde cholangiopancreatography or Percutaneous Transhepatic Biliary Drainage (PTBD). To date there is no consensus about which method is preferred. Taking that into account, the aim of this study is to compare Endoscopic Biliary Drainage (EBD) versus percutaneous transhepatic biliary drainage in patients with perihilar cholangiocarcinoma through a systematic review and metanalysis. A comprehensive search of multiple electronic databases was performed. Evaluated outcomes included technical success, clinical success, post drainage complications (cholangitis, pancreatitis, bleeding, and major complications), crossover, hospital length stay, and seeding metastases. Data extracted from the studies were used to calculate Mean Differences (MD). Seventeen studies were included, with a total of 2284 patients (EBD = 1239, PTBD = 1045). Considering resectable PCCA, the PTBD group demonstrated lower rates of crossover (RD = 0.29; 95% CI 0.07‒0.51; p = 0.009 I² = 90%), post-drainage complications (RD = 0.20; 95% CI 0.06‒0.33; p < 0.0001; I² = 78%), and post-drainage pancreatitis (RD = 0.10; 95% CI 0.05‒0.16; p < 0.0001; I² = 64%). The EBD group presented reduced length of hospital stay (RD = -2.89; 95% CI -3.35 ‒ -2,43; p < 0.00001; I² = 42%). Considering palliative PCCA, the PTBD group demonstrated a higher clinical success (RD = -0.19; 95% CI -0.27 ‒ -0.11; p < 0.00001; I² = 0%) and less post-drainage cholangitis (RD = 0.08; 95% CI 0.01‒0.15; p = 0.02; I² = 48%) when compared to the EBD group. There was no statistical difference between the groups regarding: technical success, post-drainage bleeding, major post-drainage complications, and seeding metastases.


Assuntos
Neoplasias dos Ductos Biliares , Colangite , Tumor de Klatskin , Pancreatite , Humanos , Tumor de Klatskin/cirurgia , Tumor de Klatskin/complicações , Tumor de Klatskin/patologia , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/patologia , Colangite/complicações , Colangite/patologia , Pancreatite/complicações , Pancreatite/patologia , Drenagem/efeitos adversos , Drenagem/métodos , Ductos Biliares Intra-Hepáticos/patologia , Estudos Retrospectivos
9.
J Transl Med ; 21(1): 43, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36691046

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignant disease characterized by onset occult, rapid progression, high relapse rate, and high mortality. However, data on how the tumor microenvironment (TME) regulates ICC metastasis at the transcriptomic level remains unclear. This study aimed to explore the mechanisms and interactions between hepatocytes and ICC cells. METHODS: We analyzed the interplay between ICC and liver microenvironment through cytokine antibody array analysis. Then we investigated the role of N6-methyladenosine (m6A) modification and the downstream target in vitro, in vivo experiments, and in clinical specimens. RESULTS: Our study demonstrated that cytokine CCL3, which is secreted by hepatocytes, promotes tumor metastasis by regulating m6A modification via vir-like m6A methyltransferase associated (VIRMA) in ICC cells. Moreover, immunohistochemical analyses showed that VIRMA correlated with poor outcomes in ICC patients. Finally, we confirmed both in vitro and in vivo that CCL3 could activate VIRMA and its critical downstream target SIRT1, which fuels tumor metastasis in ICC. CONCLUSIONS: In conclusion, our results enhanced our understanding of the interaction between hepatocytes and ICC cells, and revealed the molecular mechanism of the CCL3/VIRMA/SIRT1 pathway via m6A-mediated regulation in ICC metastasis. These studies highlight potential targets for the diagnosis, treatment, and prognosis of ICC.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Sirtuína 1 , Recidiva Local de Neoplasia , Colangiocarcinoma/metabolismo , Prognóstico , Ductos Biliares Intra-Hepáticos/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Hepatócitos/patologia , Citocinas , Linhagem Celular Tumoral , Microambiente Tumoral
10.
PLoS Negl Trop Dis ; 17(1): e0011062, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36693049

RESUMO

Clonorchis sinensis is an important food-borne zoonotic parasite which has been linked to biliary fibrosis and cholangiocarcinoma. However, the details of the pathogenesis of C. sinensis were unclear. To explore the role and regulatory mechanism of toll-like receptor 2 (TLR2) in C. sinensis-induced biliary fibrosis, we established the C. sinensis-infected C57BL/6 mouse model with TLR2-/- and wild type (WT) mice. The mortality rate, liver lesions, TLR2 and TGF-ß1 expression, phosphorylation of Smad2/3, AKT, p38, ERK and p65, and cytokine productions were analyzed. Furthermore, similar parameters were examined in mouse biliary epithelial cells (BECs) co-cultured with C. sinensis excretory/secretory proteins (ESPs). The results showed that TLR2 expression was enhanced significantly in C. sinensis-infected WT mice and mouse BECs. C. sinensis-infected TLR2-/- mice exhibited an increased weight and a decreased mortality rate; significantly alleviated liver lesions and biliary fibrosis, reduced numbers of myofibroblasts; decreased expression of TGF-ß1 and phosphorylation level of AKT, p38 and Smad2/3; significantly decreased production of IL-6, TNF-α and IL-4, while increased production of IFN-γ compared with C. sinensis-infected WT mice. Furthermore, C. sinensis ESPs could activate TLR2-mediated AKT and p38 pathways to increase the production of IL-6 in mouse BECs. In conclusion, these data indicate that C. sinensis infection activated TGF-ß1-Smad2/3 through TLR2-mediated AKT and p38 pathways to promote IL-6 production, which resulted in myofibroblast activation and aggravating biliary fibrosis in mice.


Assuntos
Neoplasias dos Ductos Biliares , Clonorquíase , Clonorchis sinensis , Neoplasias Hepáticas , Camundongos , Animais , Clonorchis sinensis/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Clonorquíase/parasitologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta1 , Interleucina-6/genética , Camundongos Endogâmicos C57BL , Transdução de Sinais , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Fibrose , Neoplasias Hepáticas/patologia
11.
Cancer Biol Ther ; 24(1): 2162807, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36647192

RESUMO

Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.


Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Curcumina , Humanos , Animais , Camundongos , Curcumina/farmacologia , Curcumina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Morte Celular , Apoptose , Colangiocarcinoma/tratamento farmacológico , Proliferação de Células , Pontos de Checagem da Fase G2 do Ciclo Celular , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia
12.
World J Surg Oncol ; 21(1): 16, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36658564

RESUMO

BACKGROUND: Some studies have pointed out that a wide resection margin can improve the prognosis of intrahepatic cholangiocarcinoma, but some researchers disagree and believe that a wide margin may increase complications. The optimal margin length of intrahepatic cholangiocarcinoma is controversial. METHOD: The literature was searched in PubMed, MedLine, Embase, the Cochrane Library, and Web of Science until December 31, 2021, to evaluate the postoperative outcomes of patients with different margin width after resection. Odds ratios (ORs) with 95% confidence intervals were used to determine the effect size. RESULT: A total of 11 articles were included in this meta-analysis, including 3007 patients. The narrow group had significantly lower 1-, 3-, and 5-year overall survival rates and recurrence-free survival rates than the wide group. Postoperative morbidity and prognostic factors were also evaluated. CONCLUSION: A resection margin width of over 10 mm is recommended in intrahepatic cholangiocarcinoma patients, especially in patients with negative lymph node and early tumor stage. When the resection margin width cannot be greater than 10 mm, we should ensure that the resection margin width is greater than 5 mm.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Margens de Excisão , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Prognóstico , Hepatectomia , Ductos Biliares Intra-Hepáticos/patologia , Estudos Retrospectivos
13.
Int J Mol Med ; 51(3)2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36660943

RESUMO

13­cis­retinoic acid (13CRA), a Food and Drug Administration­approved drug for severe acne, is currently being investigated for its potential use in skin cancer prevention. 13CRA has been reported to exhibit antitumor effects against various types of cancer cells, both in vitro and in vivo. However, to the best of our knowledge, no information is yet available regarding the effects of 13CRA on cholangiocarcinoma (CCA), a malignancy of the bile duct epithelia. Currently, there are no reliably effective therapeutic options for metastatic CCA. The present study thus aimed to evaluate the effects of 13CRA on the self­renewal, migration, invasion and adhesion of CCA cells, and also investigated the underlying mechanisms. The results revealed that 13CRA suppressed cell proliferation via the inhibition of the self­renewal ability of CCA cells. 13CRA induced cell cycle arrest at the G2/M phase in KKU­100 and KKU­213B CCA cells through the regulation of cell cycle­regulatory genes and proteins. 13CRA reduced the cell migratory ability of both cell lines via the modulation of the genes and proteins associated with epithelial­mesenchymal transition. 13CRA also inhibited the invasive and adhesive abilities of CCA cells via the suppression of genes and proteins associated with the invasion and adhesion of CCA cells. On the whole, these results suggested that 13CRA exerts suppressive effects on CCA cell proliferation, migration, adhesion and invasion.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Isotretinoína/farmacologia , Isotretinoína/uso terapêutico , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Proliferação de Células , Movimento Celular/genética , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/patologia
14.
BMC Gastroenterol ; 23(1): 22, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681801

RESUMO

BACKGROUND: N7-methylguanosine (m7G) is present in a wide variety of organisms and has important roles. m7G has been reported to be involved in multiple biological processes, and recent studies have reported that changes in RNA modifications result in tumor cellular transformation and cancer, such as colon adenocarcinoma, lung cancer, and intrahepatic cholangiocarcinoma. However, little is known about the function of the m7G in colon adenocarcinoma. METHODS: We established two clusters based on the expression of all genes associated with m7G to explore the expression pattern of 31 key regulatory factors of m7G RNA and assess the prognostic value of regulatory factors. Wilcoxon test and differential box line plots were applied for bioinformatics analysis. Receiver Operating and Kaplan‒Meier curves were utilized to evaluate the prognostic value. Finally, four genes' expression in the colon cancer cell line was confirmed by qRT-PCR. RESULTS: From The Cancer Genome Atlas database, we found that the expression levels of 25 out of the 31 key N7-methylguanosine RNA modification regulators were significantly different in colon adenocarcinoma. According to 25 methylation regulators' expression, we identified two subgroups by consensus clustering, in which the prognosis was worse in Group 2 than in Group 1 and was significantly correlated with age. Cluster 2 was significantly enriched in tumor-associated pathways, and immune cells were highly infiltrated in Cluster 1 but weakly infiltrated in Cluster 2. Further results indicated that this risk profile may serve as a standalone predictive factor for colon adenocarcinoma, and the four genetic risk profiles' prognostic relatedness was successfully verified through Gene Expression Omnibus dataset. At last, A nomogram for prognosis was created according to age, sex, histological grading, clinicopathological staging, and hazard score to accurately predict patient prognosis in colon adenocarcinoma. We successfully validated the differential expression of four genes using qRT-PCR. CONCLUSIONS: In the present study, we revealed the important contribution of key regulators associated with m7G RNA modifications based on all gene expression in colon adenocarcinoma and developed a signature of risk that serves as a promising prognostic marker for patients with colon adenocarcinoma.


Assuntos
Adenocarcinoma , Neoplasias dos Ductos Biliares , Neoplasias do Colo , Humanos , Neoplasias do Colo/genética , Prognóstico , Adenocarcinoma/genética , Ductos Biliares Intra-Hepáticos , Expressão Gênica
16.
Phytomedicine ; 109: 154575, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610163

RESUMO

BACKGROUND: High levels of glycolysis supply large quantities of energy and biological macromolecular raw materials for cell proliferation. Triptolide (TP) is a kind of epoxy diterpene lactone extracted from the roots, flowers, leaves, or grains of the Celastraceae plant, Tripterygium wilfordii. TP has multiple biological activities, including anti-inflammatory, immunologic suppression, and anti-cancer effects. Nevertheless, it is little known regarding its anti-intrahepatic cholangiocarcinoma (ICC) growth, and the mechanism still require exploration. PURPOSE: This research explored the effect of TP on ICC growth and investigated whether TP inhibits glycolysis via the AKT/mTOR pathway. METHODS: Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8), clonogenic assay, and flow cytometry. The underlying molecular mechanism was identified by determining glucose consumption, ATP production, lactate production, hexokinase (HK) and pyruvate kinase (PK) activity, and Western blot analysis. A rapid ICC model of AKT/YapS127A oncogene coactivation in mice was used to clarify the effect of TP treatment on tumor growth and glycolysis. RESULTS: The results showed that TP treatment significantly inhibited ICC cell proliferation and glycolysis in a dose- and time-dependent manner(P < 0.05). Further analysis suggested that TP suppressed ICC cell glycolysis by targeting AKT/mTOR signaling. Additionally, we found that TP inhibits tumor growth and glycolysis in AKT/YapS127A mice(P < 0.05). CONCLUSION: Taken together, we revealed that TP suppressed ICC growth by suppressing glycolysis via the AKT/mTOR pathway and may provide a potential therapeutic target for ICC treatment.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Diterpenos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Colangiocarcinoma/metabolismo , Proliferação de Células , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Glicólise , Linhagem Celular Tumoral
17.
Mymensingh Med J ; 32(1): 257-260, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36594330

RESUMO

Diagnosis of primary sclerosing cholangitis (PSC) is often very difficult and may have a suspicion with altered liver functions. PSC is known to be associated with inflammatory bowel disease. This article presents a case study of a 70 years old male patient who presented with obstructive jaundice with recurrent episode of cholangitis in June 2019 at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Evaluation revealed beaded appearance in MRCP with positive relevant markers which raised suspicion of PSC and it was confirmed by biopsy and histopathology of the affected segment in biliary tree. The importance of early detection of primary sclerosing cholangitis in an effort to decrease the morbidity and mortality from cholangiocarcinoma will also be emphasized and our management according to local protocol and outcome of this patient.


Assuntos
Neoplasias dos Ductos Biliares , Colangite Esclerosante , Icterícia Obstrutiva , Humanos , Idoso , Icterícia Obstrutiva/diagnóstico , Icterícia Obstrutiva/etiologia , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Bangladesh , Ductos Biliares Intra-Hepáticos
18.
World J Surg Oncol ; 21(1): 9, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647103

RESUMO

BACKGROUND: Budd-Chiari syndrome (BCS) is a rare vascular disorder of the liver, and acute and secondary BCS is even rarer. CASE PRESENTATION: A 62-year-old man with perihilar cholangiocarcinoma of Bismuth type IIIa underwent right hemi-hepatectomy with caudate lobectomy and pancreatoduodenectomy. Adjuvant chemoradiotherapy was performed due to a positive hepatic ductal margin. Subsequently, the disease passed without recurrence. The patient visited for acute onset abdominal pain at the 32nd postoperative month. Multidetector-row computed tomography (MDCT) showed stenosis of the left hepatic vein (LHV) root, which was the irradiated field, and thrombotic occlusion of the LHV. The patient was diagnosed with acute BCS caused by adjuvant radiotherapy. Although anticoagulation therapy was performed, the patient complained of sudden upper abdominal pain again. MDCT showed an enlarged LHV thrombus and hepatomegaly. The patient was diagnosed with exacerbated acute BCS, and stenting for the stenotic LHV root was performed with a bare stent. Although stenting for the LHV root was very effective, restenosis occurred twice due to thrombus in the existing stent, so re-stenting was performed twice. The subsequent clinical course was acceptable without recurrence or restenosis of the LHV root as of 6 months after the last stenting using a stent graft. CONCLUSION: Although no case of BCS caused by radiotherapy has yet been reported, the present case showed that late side effect of radiotherapy can cause hepatic vein stenosis and secondary BCS.


Assuntos
Neoplasias dos Ductos Biliares , Síndrome de Budd-Chiari , Tumor de Klatskin , Masculino , Humanos , Pessoa de Meia-Idade , Síndrome de Budd-Chiari/complicações , Síndrome de Budd-Chiari/cirurgia , Radioterapia Adjuvante , Tumor de Klatskin/etiologia , Tumor de Klatskin/cirurgia , Constrição Patológica , Veias Hepáticas , Neoplasias dos Ductos Biliares/radioterapia , Neoplasias dos Ductos Biliares/complicações , Dor Abdominal
19.
Nat Commun ; 14(1): 109, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611024

RESUMO

Bile duct cancer is the second most common primary liver cancer, with most diagnoses occurring in the advanced stages. This leads to a poor survival rate, which means a technique capable of reliably detecting pre-cancer in the bile duct is urgently required. Unfortunately, radiological imaging lacks adequate accuracy for distinguishing dysplastic and benign biliary ducts, while endoscopic techniques, which can directly assess the bile duct lining, often suffer from insufficient sampling. Here, we report an endoscopic optical light scattering technique for clinical evaluation of the malignant potential of the bile duct. This technique employs an ultraminiature spatial gating fiber optic probe compatible with cholangioscopes and endoscopic retrograde cholangiopancreatography (ERCP) catheters. The probe allowed us to investigate the internal cellular composition of the bile duct epithelium with light scattering spectroscopy (LSS) and phenotypic properties of the underlying connective tissue with diffuse reflectance spectroscopy (DRS). In a pilot in vivo double-blind prospective study involving 29 patients undergoing routine ERCP procedures, the technique detected malignant transformation with 97% accuracy, showing that biliary duct pre-cancer can be reliably identified in vivo non-invasively.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Estudos Prospectivos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos , Análise Espectral
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