RESUMO
The liver excretes bile through the biliary system, which has a complicated anatomical structure. Cholangiocarcinoma, a malignant bile duct epithelial tumor, is separated into intrahepatic and extrahepatic portions depending on the structure of the bile duct and exhibits both similarities and varieties in patient presentations and staging. The three main macroscopic characteristics of cholangiocarcinoma-mass formating, intraductal growth, and periductal infiltrating types-allow pathologists and surgeons to see and analyze the cancerous tissue. The majority of cholangiocarcinoma patients are in advanced stages and poor prognosis. Although surgery is the main treatment option, target therapy based on molecular pathology background offers hope for improving patient's prognosis.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Colangiocarcinoma/genética , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-HepáticosRESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) arises from bile ducts within the liver. Thailand has the highest incidence of CCA worldwide, with a high mortality rate. Early diagnosis and accurate prognostic stratification can improve overall survival. We aim to modify the AJCC/UICC 8th edition staging system for iCCA by creating the Khon Kaen University (KKU) staging system for more precise patient stratification and prognostic prediction. METHODS: A total of 298 iCCA patients who underwent hepatectomy were included in this retrospective study at the Srinagarind Hospital, Khon Kaen University, Thailand. Univariate and multivariate analysis were performed to examine survival rate, hazard ratio, and prognostic factors. RESULTS: Univariate and multivariate analysis of the cohort showed that growth patterns, histological type, histological grade, lymph node metastasis and distant metastasis were independent prognostic factors when compared to the respective reference groups. The 8th AJCC staging system incorporated growth patterns into the KKU staging system. This model modified AJCC stages I, II, and III for better prediction of patient survival. CONCLUSION: Growth patterns were incorporated to improve the 8th AJCC staging system for prognostication of iCCA patients in Northeast Thailand. We propose the KKU staging system as an alternative model for iCCA staging to augment the accuracy of survival prognostication.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Neoplasias dos Ductos Biliares/patologia , Estudos Retrospectivos , Tailândia , Estadiamento de Neoplasias , Prognóstico , Ductos Biliares Intra-Hepáticos/cirurgiaRESUMO
Glucagon-like peptide 1 receptor (GLP-1R) agonist is an emerging anti-diabetic medication whose effects on the risk and progression of cholangiocarcinoma (CCA) are controversial. This study aimed to elucidate the roles of GLP-1R and its agonists on intrahepatic CCA (iCCA) progression. Expressions of GLP-1R in iCCA tissues investigated by immunohistochemistry showed that GLP-1R expressions were significantly associated with poor histological grading (P = 0.027). iCCA cell lines, KKU-055 and KKU-213A, were treated with exendin-4 and liraglutide, GLP-1R agonists, and their effects on proliferation and migration were assessed. Exendin-4 and liraglutide did not affect CCA cell proliferation in vitro, but liraglutide significantly suppressed the migration of CCA cells, partly by inhibiting epithelial-mesenchymal transition. In contrast, liraglutide significantly reduced CCA tumor volumes and weights in xenografted mice (P = 0.046). GLP-1R appeared downregulated when CCA cells were treated with liraglutide in vitro and in vivo. In addition, liraglutide treatment significantly suppressed Akt and STAT3 signaling in CCA cells, by reducing their phosphorylation levels. These results suggested that liraglutide potentially slows down CCA progression, and further clinical investigation would benefit the treatment of CCA with diabetes mellitus.
Assuntos
Neoplasias dos Ductos Biliares , Movimento Celular , Proliferação de Células , Colangiocarcinoma , Transição Epitelial-Mesenquimal , Receptor do Peptídeo Semelhante ao Glucagon 1 , Liraglutida , Ensaios Antitumorais Modelo de Xenoenxerto , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Humanos , Animais , Linhagem Celular Tumoral , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Masculino , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Progressão da Doença , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Exenatida/farmacologia , Exenatida/uso terapêutico , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Background: Diabetes mellitus (DM) is associated with the increased risk of development and the advancement of cholangiocarcinoma (CCA). High glucose levels were previously shown for upregulating interleukin-1ß (IL-1ß) in CCA cells with unclear functions. The present study, thus, aimed to investigate molecular mechanisms linking DM to CCA progression, with IL-1ß hypothesized as a communicating cytokine. Methods: CCA cells were cultured in media with normal (5.6 mM) or high (25 mM) glucose, resembling euglycemia and hyperglycemia, respectively. Expressions of IL-1ß and IL-1 receptor (IL-1R) in CCA tissues from patients with and without DM were examined using immunohistochemistry. Functional analyses of IL-1ß were performed using siRNA and recombinant human IL-1R antagonist (rhIL-1RA), in which Western blots investigated the knockdown efficacy. BALB/c Rag-2-/- Jak3-/- (BRJ) mice were implanted with CCA xenografts to investigate hyperglycemia's effects on CCA growth and the anti-tumor effects of IL-1RA. Results: CCA tumors from patients with hyperglycemia showed significantly higher IL-1ß expression than those from non-DM patients, while IL-1ß was positively correlated with fasting blood glucose (FBG) levels. CCA cells cultured in high glucose showed increased IL-1ß expression, resulting in increased proliferation rates. Suppressing IL-1ß signaling by si-IL-1ß or rhIL-1RA significantly reduced CCA cell proliferation in vitro. Anakinra, a synthetic IL-1RA, also exerted significant anti-tumor effects in vivo and significantly reversed the effects of hyperglycemia-induced growth in CCA xenografts. Conclusions: IL-1ß plays a crucial role in CCA progression in a high-glucose environment. Targeting IL-1ß might, then, help improve therapeutic outcomes of CCA in patients with DM and hyperglycemia.
RESUMO
BACKGROUND/AIM: Diabetes mellitus (DM) is an established risk for hepatocellular carcinoma (HCC), with unclarified mechanisms. This study investigated the effects of hyperglycemia on O-GlcNacylation in hepatocytes and its associations with hepatocarcinogenesis. MATERIALS AND METHODS: Mouse and human HCC cell lines were used in an in vitro model of hyperglycemia. Western blotting was used to determine the effects of high glucose on O-GlcNacylation in HCC cells. Twenty 4-week-old C3H/HeNJcl mice were randomized into four groups: non-DM control, non-DM plus diethylnitrosamine (DEN), DM, and DM plus DEN. DM was induced using intraperitoneal injection of a single high dose of streptozotocin. DEN was used to induce HCC. All mice were euthanized at week 16 after DM induction, and the liver tissues were histologically examined using hematoxylin and eosin, and immunohistochemistry. RESULTS: High glucose increased O-GlcNacylated proteins in mouse and human HCC cell lines compared with those cultured at normal glucose concentration. Mice with hyperglycemia or DEN treatment had increased O-GlcNacylated proteins in hepatocytes. No gross tumors were evident at the end of the experiment but hepatic morbidity was observed. Mice with hyperglycemia and DEN treatment showed greater histological morbidity in their livers, i.e. increased nuclear size, hepatocellular swelling and sinusoidal dilatation, compared with mice in the DM group or treated with DEN alone. CONCLUSION: Hyperglycemia increased O-GlcNAcylation in both in vitro and animal models. Increased O-GlcNAcylated proteins may be associated with hepatic histological morbidities which then promote HCC development in carcinogen-induced tumorigenesis.
Assuntos
Carcinoma Hepatocelular , Hiperglicemia , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Camundongos Endogâmicos C3H , Carcinógenos/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Hepatócitos , Carcinogênese , GlucoseRESUMO
Cholangiocarcinoma (CCA) is the most prevalent malignancy in Thailand, with unfortunate late diagnosis and frequent metastatic disease outcomes. An accurate tissue diagnosis is the first and most important step in the treatment of CCA. Tissue quality and preservation during the pre-analytical phase play major roles in the proper histological evaluation and potential biomarker testing. This study evaluated the impact of using the "Cholangiocarcinoma Screening and Care Program (CASCAP)" container, as an innovative tool to address pre-analytical challenges faced by pathology laboratories in Thailand. This is a comparison study examining the quality of CCA specimens using the CASCAP container vs. the conventional method, using hematoxylin and eosin (H&E) and immunohistochemistry (IHC). CCA tissue quality using the CASCAP container significantly reduced artifact deposition while improving the cellular structure and nuclear and cytoplasmic morphologies. The immunohistochemical expression of cytokeratin 19 (CK19), a prognostic marker in CCA, significantly improved in the CASCAP container group in comparison with the conventional method. This innovation is proven to significantly enhance the CCA tissue quality diagnostics and prognostic biomarker testing, hence improving overall cancer care, diagnosis, and treatment in Thailand.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patologia , Humanos , Programas de Rastreamento , TailândiaRESUMO
Aim: This study aims to improve the classification performance of the eighth American Joint Committee on Cancer (AJCC) staging system for perihilar cholangiocarcinoma (pCCA) by proposing the Khon Kaen University (KKU) staging system developed in cholangiocarcinoma-prevalent Northeast Thailand. Method: Four hundred eighty-eight patients with pCCA who underwent partial hepatectomy between 2002 and 2017 at the Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand, were included. Overall survival (OS) related to clinicopathological features was analyzed using the Kaplan-Meier method. Logrank test was performed in univariate analysis to compare OS data of clinicopathological features to determine risk factors for poor survival. Significant features were further analyzed by multivariate analysis (Cox regression) to identify prognostic factors which were then employed to modify the eighth AJCC staging system. Results: Multivariate analysis showed that growth pattern (HR = 4.67-19.72, p < 0.001), moderately and poorly differentiated histological grades (HR = 2.31-4.99, p < 0.05 and 0.001, respectively), lymph node metastasis N1 and N2 (HR = 1.37 and 2.18, p < 0.05 and 0.01, respectively), and distant metastasis (HR = 2.11, p < 0.001) were independent factors when compared to their respective reference groups. There was a clear separation of patients with pCCA into KKU stage: I [OS = 116 months (mo.)], II (OS = 46 mo.), IIIA (OS = 24 mo.), IIIB (11 mo.), IVA (OS = 7 mo.), and IVB (OS = 6 mo.). Conclusion: The new staging system was based on the incorporation of growth patterns to modify the eighth AJCC staging system. The classification performance demonstrated that the KKU staging system was able to classify and distinctly separate patients with pCCA into those with good and poor outcomes. It was also able to improve the stratification performance and discriminative ability of different stages of pCCA classification better than the eighth AJCC staging system. Hence, the KKU staging system is proposed as an alternative model to augment the accuracy of survival prognostication and treatment performance for patients with pCCA.
RESUMO
Patients with distal cholangiocarcinoma (dCCA) generally have poor outcomes because of late presentation and diagnosis. Therefore, prognostic factors for predicting outcomes are essential to improve therapeutic strategies and quality of life. Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic predictor in several cancers. However, their role in dCCA is still unclear. This study aimed to evaluate the association of TILs with outcome in patients with dCCA. Fifty-two patients were evaluated for the percentage rate of TILs in their cancers, and a median TIL level was used to divide the patients into two groups. Survival, multivariate, and correlation analyses were performed to determine the prognostic factors. Results showed that a low TIL level was associated with poor survival. Multivariate analysis revealed TILs as an independent factor for poor outcome. Moreover, TILs were markedly correlated with growth patterns, and both were applied to classify patients with dCCA. Subgroups of TILs with growth pattern incorporation improved stratification performance in separating good from poor patient outcomes. This study suggested that TILs could be a prognostic factor for predicting survival and for clustering patients with dCCA to improve prognostication capability. This finding may be incorporated into a new staging system for stratifying dCCA in Thailand.
RESUMO
Distal cholangiocarcinoma (dCCA) is a rare type of CCA in Asia, even in Opisthorchis viverrini-prevalent Northeastern Thailand. The clinical ambiguity and imprecision of diagnosis surrounding this malignancy result in high mortality due often to advanced/metastatic disease on presentation. We aim to identify a prognostic factor that can improve the performance stratification and influence the outcome of dCCA patients after curative resection. A total of 79 patients who underwent curative-intended surgery for dCCA was enrolled. Possible risk factors for survival were analyzed with log-rank test, and independent factors with Cox regression model. dCCA patients were staged and classified according to the 8th edition the American Joint Committee on Cancer (AJCC) Staging Manual. Results were then compared with the revised classification employing the prognostic factor identified from multivariate analysis. Multivariate analysis revealed that growth pattern (p < 0.01) and distant metastasis (p = 0.012) were independent factors. Growth patterns comprise intraductal (ID), periductal infiltrating (PI), mass-forming (MF), and mixed types. When dCCA patients were grouped into those having good and poor outcomes (with and without ID components, respectively). The survival outcomes significantly differed among patients with and without ID components, which was better than with the 8th AJCC staging system in our cohort. Furthermore, Chi-square test showed that patterns without ID components (PI, MF, PI + MF) correlated with lymph node and distant metastasis. Therefore, classification of dCCA patients after curative-intended surgical resection based on growth pattern provides additional beneficial information for the prediction of survival in dCCA patients.