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1.
Surg Oncol Clin N Am ; 32(1): 83-99, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36410923

RESUMO

Most of the patients with gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (iCCA), and peri-hilar cholangiocarcinoma (pCCA) present with advanced disease. Complete staging with multiphasic liver imaging is essential to determine the extent of disease. Operative goals should include a margin-negative resection, portal lymphadenectomy for staging, and sufficient remnant liver volume. Biliary tract malignancies have distinct mutational drivers (GBC and pCCA = ERBB2 in 20%; iCCA = fibroblast growth factor receptor 2 or isocitrate dehydrogenase 1 in 20%) amenable to therapy with inhibitors. Clinical trials assessing neoadjuvant, peri-operative, and adjuvant treatments continue to evolve and now include targeted inhibitors and the integration of hepatic arterial infusion.


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Neoplasias da Vesícula Biliar , Humanos , Neoplasias do Sistema Biliar/cirurgia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Colangiocarcinoma/patologia , Neoplasias da Vesícula Biliar/cirurgia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia
2.
Cancer Lett ; 553: 215980, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36336149

RESUMO

Cholangiocarcinoma (CCA) is the most common primary biliary malignancy with an adverse prognosis. Although its incidence is relatively low, early diagnosis is difficult due to the lack of specific symptoms. Current treatment options for CCA are limited, resulting in a low curative rate. Circular RNAs (circRNAs) have become a new research hotspot in recent years, and they are frequently dysregulated in CCA and may become therapeutic targets and prognostic biomarkers of CCA. Accumulating evidence has demonstrated that numerous dysregulated circRNAs are vital players in the etiopathogenesis of CCA. Aberrant expression of specific circRNAs was correlated with unfavourable clinical characteristics in CCA. Many studies have found that circRNAs are involved in the progression and development of CCA through various mechanisms, including competitive inhibition of miRNAs via the competing endogenous RNA (ceRNA) network, interaction with RNA-binding proteins (RBPs), activation of cancer-related signalling pathways, and regulation of proteins and peptides. Additionally, some circRNAs are involved in the inflammatory microenvironment of CCA and play a crucial role in chemotherapy drug resistance. Thus, they are essential for the early diagnosis and prediction of CCA, and more attention should be given to the roles and mechanisms of circRNAs in CCA. In this review, we summarize the abnormal expression of circRNAs in CCA and the specific inflammatory microenvironment involved, as well as the roles and mechanisms of circRNAs in the occurrence and development of CCA. We also review the latest knowle dge on circRNAs in CCA and discuss the challenges associated with the introduction of circRNAs into clinical practice and their potential clinical value.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , MicroRNAs , Humanos , RNA Circular/genética , Colangiocarcinoma/patologia , MicroRNAs/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Microambiente Tumoral/genética
3.
Abdom Radiol (NY) ; 47(3): 981-997, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34978593

RESUMO

Cholangiocarcinoma (CCA) is the second most common primary hepatobiliary malignancy and presents as three separate morphological subtypes; namely mass-forming, periductal-infiltrating, and intraductal-growing patterns. Each of these subtypes have distinct imaging characteristics, as well as a variety of benign and malignant mimics, making accurate diagnosis of CCA on imaging challenging. Whilst histopathological examination is required to arrive at a definitive diagnosis, it is still important for radiologists to be cognizant of these entities and provide reasonable differential diagnoses, as these potentially have a large impact on patient management. This pictorial essay illustrates the three morphological subtypes of CCA, as well as some important mimics for each subtype, that are encountered in clinical practice.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Diagnóstico Diferencial , Diagnóstico por Imagem , Humanos
4.
Am J Pathol ; 192(12): 1712-1724, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36456043

RESUMO

Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tree. Although studies have implicated enhancer of Zeste homolog 2 (EZH2) in CCA growth, the role of EZH2 in CCA development has not been investigated, and the mechanism for EZH2-regulated gene expression in CCA remains to be further defined. The current study used a mouse model of CCA induced by hydrodynamic tail vein injection of Notch1 intracellular domain and myristoylated-AKT plasmids. Mice with liver-specific EZH2 knockout displayed reduced CCA development. In a xenograft model, EZH2 knockdown significantly decreased CCA progression. Administration of the EZH2 inhibitor GSK126 decreased CCA tumor burden in mice. Accordingly, EZH2 depletion or inhibition reduced the growth and colony formation capability of CCA cells. Analysis of high-throughput data identified a set of 12 tumor-inhibiting genes as targets of EZH2 in CCA. The experimental results suggest that EZH2 may down-regulate these tumor-inhibiting genes through methylation of lysine 27 on histone H3 (H3K27) in the gene louses and through regulation of specific miRNAs. High mobility group box 1 was shown to facilitate the methyltransferase activity of EZH2, which is implicated in the regulation of CCA cell growth. The study shows that EZH2 promotes CCA development and progression through a complicated regulatory network involving tumor-inhibiting genes, miRNAs, and high mobility group box 1, which support targeting EZH2 as a potentially effective strategy for CCA treatment.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , MicroRNAs , Humanos , Camundongos , Animais , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação para Baixo , Metilação , Histonas , MicroRNAs/genética , Genes Supressores de Tumor , Colangiocarcinoma/genética , Modelos Animais de Doenças , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos
6.
Transpl Int ; 35: 10802, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406780

RESUMO

Cholangiocarcinoma (CCA) is currently a contraindication to liver transplantation (LT) in the United Kingdom (UK). Incidental CCA occurs rarely in some patients undergoing LT. We report on retrospective outcomes of patients with incidental CCA from six UK LT centres. Cases were identified from pathology records. Data regarding tumour characteristics and post-transplant survival were collected. CCA was classified by TNM staging and anatomical location. 95 patients who underwent LT between 1988-2020 were identified. Median follow-up after LT was 2.1 years (14 days-18.6 years). Most patients were male (68.4%), median age at LT was 53 (IQR 46-62), and the majority had underlying PSC (61%). Overall median survival after LT was 4.4 years. Survival differed by tumour site: 1-, 3-, and 5-year estimated survival was 82.1%, 68.7%, and 57.1%, respectively, in intrahepatic CCA (n = 40) and 58.5%, 42.6%, and 30.2% in perihilar CCA (n = 42; p = 0.06). 1-, 3-, and 5-year estimated survival was 95.8%, 86.5%, and 80.6%, respectively, in pT1 tumours (28.2% of cohort), and 65.8%, 44.7%, and 31.1%, respectively, in pT2-4 (p = 0.018). Survival after LT for recipients with incidental CCA is inferior compared to usual outcomes for LT in the United Kingdom. LT for earlier stage CCA has similar survival to LT for hepatocellular cancer, and intrahepatic CCAs have better survival compared to perihilar CCAs. These observations may support LT for CCA in selected cases.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transplante de Fígado , Humanos , Masculino , Feminino , Transplante de Fígado/efeitos adversos , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/etiologia , Estudos Retrospectivos , Colangiocarcinoma/cirurgia , Colangiocarcinoma/etiologia , Ductos Biliares Intra-Hepáticos/patologia
7.
J Med Life ; 15(10): 1257-1266, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36420295

RESUMO

Hepatitis C viral (HCV) treatment has rapidly advanced with the use of direct-acting antivirals (DAA), and many patients achieve sustained virological response (SVR). Although the risk of liver tumors is greatly reduced, there are still patients who achieve SVR but will progress to hepatocellular carcinoma (HCC). HCV infection is also a known risk for cholangiocellular carcinoma (CLC), although it is considered a relative infrequent liver malignancy. We report a series of five cases of CLC in patients that achieved SVR after HCV treatment with DAA. There were three women and two males with a median age of 62 years (range 49 to 77 years). Four patients had liver cirrhosis at the time of their HCV treatment. The interval from achieving SVR until CLC diagnosis varied, ranging from 4 to 36 months (median=12). Three patients presented with advanced disease and had extrahepatic spread at the time of their diagnosis. One patient had a resectable tumor, with no recurrence 4 years later. In one case, the tumor was initially considered an atypical HCC and was treated by radiofrequency ablation. Three years later, she was diagnosed with a large tumor recurrence that was demonstrated to be a CLC on liver biopsy. The last two patients were older males with HCV compensated cirrhosis diagnosed with CLC more than two years after achieving SVR. Palliative chemotherapy was started in both. Only a handful of CLC cases have been reported in HCV patients after SVR. Clinicians should take into account the possible development of an aggressive CLC.


Assuntos
Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Colangiocarcinoma/tratamento farmacológico , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Cirrose Hepática/complicações , Ductos Biliares Intra-Hepáticos
9.
Cell Death Dis ; 13(11): 967, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36400758

RESUMO

Long noncoding RNAs (lncRNAs) are a novel class of noncoding RNAs that have emerged as critical regulators and biomarkers in various cancers. Nevertheless, the expression profile and mechanistic function of lncRNAs in cholangiocarcinoma (CCA) remain unclear. Herein, we examined the expression levels of linc00976 in clinical specimens and cell lines using reverse transcription-quantitative PCR. In total, 50 patients with CCA were enrolled to analyze the correlation between linc00976 expression and clinical characteristics of CCA. Loss- and gain-of-function experiments were performed to investigate the biological effects of linc00976 on proliferation, ferroptosis, migration, and invasion of CCA cells in vitro and in vivo. In situ hybridization, RNA immunoprecipitation, bioinformatic databases, RNA pull-down assay, a dual-luciferase reporter assay, mRNA sequencing, chromatin immunoprecipitation-PCR, and rescue experiments were performed to elucidate the underlying mechanisms of linc00976-induced competitive endogenous RNA regulatory networks. We characterized a novel and abundant lncRNA, linc00976, that functions as a pro-oncogenic regulator of CCA progression. Compared with normal controls, linc00976 was dramatically upregulated in CCA tissue samples and cell lines. Patients with CCA exhibiting high linc00976 expression had a highly advanced clinical stage, substantial lymph node metastasis, and poor overall survival. Knockdown of linc00976 significantly repressed proliferation and metastasis and promoted ferroptosis of CCA cells both in vitro and in vivo, whereas linc00976 overexpression exerted the opposite effect. Mechanistically, linc00976 competitively interacted with miR-3202 to upregulate GPX4 expression, thus contributing to the malignant biological behavior of CCA cells. Moreover, we demonstrated that JUND specifically interacts with the linc00976 promoter and activates linc00976 transcription. Accordingly, JUND promotes linc00976 transcription, and linc00976 plays a crucial role in accelerating CCA tumorigenesis and metastasis and inhibiting ferroptosis by modulating the miR-3202/GPX4 axis. These findings suggest that targeting linc00976 may afford a promising therapeutic strategy for patients with CCA.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Ferroptose , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Ferroptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Proteínas Proto-Oncogênicas c-jun/metabolismo
10.
BMC Cancer ; 22(1): 1222, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36443693

RESUMO

INTRODUCTION: Clinicians increasingly perform laparoscopic surgery for intrahepatic cholangiocarcinoma (ICC). However, this surgery can be difficult in patients with advanced-stage ICC because of the complicated procedures and difficulty in achieving high-quality results. We compared the effects of a three-step optimized procedure with a traditional procedure for patients with advanced-stage ICC. METHODS: Forty-two patients with advanced-stage ICC who received optimized laparoscopic hemihepatectomy with lymph node dissection (LND, optimized group) and 84 propensity score-matched patients who received traditional laparoscopic hemihepatectomy plus LND (traditional group) were analyzed. Surgical quality, disease-free survival (DFS), and overall survival (OS) were compared. RESULTS: The optimized group had a lower surgical bleeding score (P = 0.038) and a higher surgeon satisfaction score (P = 0.001). Blood loss during hepatectomy was less in the optimized group (190 vs. 295 mL, P < 0.001). The optimized group had more harvested LNs (12.0 vs. 8.0, P < 0.001) and more positive LNs (8.0 vs. 5.0, P < 0.001), and a similar rate of adequate LND (88.1% vs. 77.4%, P = 0.149). The optimized group had longer median DFS (9.0 vs. 7.0 months, P = 0.018) and median OS (15.0 vs. 13.0 months, P = 0.046). In addition, the optimized group also had a shorter total operation time (P = 0.001), shorter liver resection time (P = 0.001), shorter LND time (P < 0.001), shorter hospital stay (P < 0.001), and lower incidence of total morbidities (14.3% vs. 36.9%, P = 0.009). CONCLUSIONS: Our optimization of a three-step laparoscopic procedure for advanced ICC was feasible, improved the quality of liver resection and LND, prolonged survival, and led to better intraoperative and postoperative outcomes.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Laparoscopia , Humanos , Laparoscopia/efeitos adversos , Colangiocarcinoma/cirurgia , Hepatectomia/efeitos adversos , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos
11.
J Exp Clin Cancer Res ; 41(1): 331, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36443822

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of the extracellular (ECM) matrix components. Liver fibroblasts close to the tumor, activated by transforming growth factor (TGF)-ß1 and expressing high levels of α-smooth muscle actin (α-SMA), become cancer-associated fibroblasts (CAFs). CAFs are deputed to produce and secrete ECM components and crosstalk with cancer cells favoring tumor progression and resistance to therapy. Overexpression of Notch signaling is implicated in CCA development and growth. The study aimed to determine the effectiveness of the Notch inhibitor, Crenigacestat, on the surrounding microenvironment of iCCA. METHODS: We investigated Crenigacestat's effectiveness in a PDX model of iCCA and human primary culture of CAFs isolated from patients with iCCA. RESULTS: In silico analysis of transcriptomic profiling from PDX iCCA tissues treated with Crenigacestat highlighted "liver fibrosis" as one of the most modulated pathways. In the iCCA PDX model, Crenigacestat treatment significantly (p < 0.001) reduced peritumoral liver fibrosis. Similar results were obtained in a hydrodynamic model of iCCA. Bioinformatic prediction of the upstream regulators related to liver fibrosis in the iCCA PDX treated with Crenigacestat revealed the involvement of the TGF-ß1 pathway as a master regulator gene showing a robust connection between TGF-ß1 and Notch pathways. Consistently, drug treatment significantly (p < 0.05) reduced TGF-ß1 mRNA and protein levels in tumoral tissue. In PDX tissues, Crenigacestat remarkably inhibited TGF-ß signaling and extracellular matrix protein gene expression and reduced α-SMA expression. Furthermore, Crenigacestat synergistically increased Gemcitabine effectiveness in the iCCA PDX model. In 31 iCCA patients, TGF-ß1 and α-SMA were upregulated in the tumoral compared with peritumoral tissues. In freshly isolated CAFs from patients with iCCA, Crenigacestat significantly (p < 0.001) inhibited Notch signaling, TGF-ß1 secretion, and Smad-2 activation. Consequently, Crenigacestat also inactivated CAFs reducing (p < 0.001) α-SMA expression. Finally, CAFs treated with Crenigacestat produced less (p < 005) ECM components such as fibronectin, collagen 1A1, and collagen 1A2. CONCLUSIONS: Notch signaling inhibition reduces the peritumoral desmoplastic reaction in iCCA, blocking the TGF-ß1 canonical pathway.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Fator de Crescimento Transformador beta1 , Ecossistema , Fígado , Ductos Biliares Intra-Hepáticos , Fibrose , Microambiente Tumoral
12.
Asian Pac J Cancer Prev ; 23(11): 3851-3857, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36444598

RESUMO

BACKGROUND: The Memorial Symptom Assessment Scale-Short Form (MSAS-SF), a standard instrument for assessing cancer patients' symptoms, has been validated in numerous languages. However, it has not been validated in Thai. OBJECTIVES: The purpose of this study was to translate the MSAS-SF into Thai and determine its psychometric properties in Cholangiocarcinoma (CCA) patients. METHODS: The MSAS-SF was translated into Thai, and 231 CCA patients completed the questionnaires, which included baseline characteristics, T-MSAS-SF, Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep), and the Hospital Anxiety and Depression Scale (HADS). Cronbach's alpha coefficient was used to assess reliability for internal consistency. For convergent validity, Pearson's correlation coefficient was used to calculate the relationship between the T-MSAS-SF and the T-CaSUN, HADS, and FACT-Hep subscales. RESULTS: Subscale and total T-MSAS-SF internal consistency reliability was moderately high, with Cronbach alpha coefficients ranging from 0.76 to 0.87. For convergent validity, the majority of T-MSAS-SF scores had moderate to low inverse correlation with FACT-Hep, HADS T-CaSUN subscales with the correlation coefficients-0.10 to -0.68 (p<0.05), reflecting that they were measuring a similar construct. CONCLUSION: Our findings showed that the T-MSAS-SF has acceptable validity and reliability to assess the psychometric properties of early to advance stage CCA patients during treatment and early post-treatment stage.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Reprodutibilidade dos Testes , Avaliação de Sintomas , Tailândia , Colangiocarcinoma/diagnóstico , Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Intra-Hepáticos
14.
Eur J Radiol ; 157: 110603, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36395677

RESUMO

BACKGROUND: Most cases of extrahepatic cholangiocarcinoma (ECC) show various degrees of hyperintensity on diffusion-weighted imaging (DWI) and hypointensity on apparent diffusion coefficient (ADC). However, the factors influencing ADC values in ECC have not yet been explored extensively. Therefore, this study explored the independent factors influencing ADC values in ECC. METHODS: A total of 88 patients with ECC confirmed by surgical pathology were retrospectively assessed. All patients underwent abdominal magnetic resonance imaging (MRI) at 3.0 T and ADC values of the tumor were measured. The correlation between ADC values and multiple clinicopathological features in ECC was analyzed, and independent factors influencing the ADC values in ECC were explored further. RESULTS: The ADC value of the tumor showed a significant difference in different perineural invasion group (p = 0.048), microvascular invasion group (p = 0.001), vascular endothelial growth factor expression group (p < 0.001), lymphatic status group (p = 0.003), and differentiation degree (DD) group (p < 0.001). However, there were no significant differences in different sex (p = 0.715), tumor location (p = 0.659), and degree of T stage (p = 0.879). Moreover, ADC value was negatively correlated with microvascular density (r = -0.725, p < 0.001) and lesion size (r = -0.244, p = 0.023). Nevertheless, there was no correlation between ADC value and patient age (r = 0.026, p = 0.812). Further regression analysis indicated that ADC value was independently associated with pathological DD of ECC (R2 = 0.678, p < 0.001) but not with other clinicopathological factors (p > 0.05). CONCLUSION: ADC value of ECC is independently correlated with pathological DD of ECC, indicating that ADC value is a potential imaging biomarker for predicting the degree of ECC malignancy.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular , Colangiocarcinoma/diagnóstico por imagem , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos
15.
BMC Cancer ; 22(1): 1178, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384474

RESUMO

BACKGROUND: Biliary tract cancer (BTC) includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, gallbladder cancer, and ampulla of Vater cancer (AVC). Although BTC is rare in the US, incidence is increasing and elevated in certain populations. This study examined BTC epidemiology in the US by age, sex, race/ethnicity, geographic region, and anatomic site. METHODS: BTC incidence, prevalence, mortality, and survival from 2001 to 2015 were evaluated using the National Cancer Institute's Surveillance, Epidemiology, and End Results Program and the Centers for Disease Control and Prevention's National Program of Cancer Registries databases. Incidence and mortality rates were calculated and reported as age-standardized rates. Data were assessed by age, anatomic sites, geographic region, and race/ethnicity, and a joinpoint regression model was used to predict trends for age-adjusted BTC incidence and mortality rates. RESULTS: BTC incidence increased during the study period (annual percent change = 1.76, 95% confidence interval [1.59-1.92]), with the highest increase in ICC (6.65 [6.11-7.19]). Incidence of unspecified BTC initially increased but has recently begun to drop. Hispanic, Asian/Pacific Islander, Black, or American Indian/Alaska Native race/ethnicity was associated with higher BTC mortality rates than White race/ethnicity. Patients with ICC had the highest mortality rate (age-standardized rate = 1.87/100,000 person-years [1.85-1.88]). Five-year survival was 15.2% for all BTC, ranging from 8.5% (ICC) to 34.5% (AVC), and patients with distant disease at diagnosis had lower survival (3%) compared with those with regional (19.1%) or locally advanced disease (31.5%). CONCLUSIONS: BTC incidence increased, survival was low across all subtypes, and mortality was greatest in patients with ICC. This underscores the serious, increasing unmet need among patients with BTC. Treatment options are limited, although clinical studies investigating immunotherapy, targeted therapies, and alternative chemotherapy combinations are ongoing. Epidemiological insights may improve patient care and inform the integration of novel therapies for BTC.


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Neoplasias da Vesícula Biliar , Estados Unidos/epidemiologia , Humanos , Neoplasias do Sistema Biliar/epidemiologia , Colangiocarcinoma/epidemiologia , Colangiocarcinoma/terapia , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias dos Ductos Biliares/epidemiologia , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos
16.
FASEB J ; 36(12): e22647, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36350008

RESUMO

Cholangiocarcinoma (CCA) is a group of tumors that arise along the human biliary duct tree, ranking second in primary hepatic malignancies. Intrahepatic CCA (iCCA) represents about 10%-20% of CCAs. There is an increasing body of evidence suggesting that iCCAs' incidence and mortality have been increasing globally over the past few decades. In this study, we found that the EIF3H expression level in iCCA tissues was significantly increased compared to the adjacent non-cancerous tissues by immunohistochemistry analysis (IHC). A similar tendency of EIF3H mRNA and protein level was confirmed in iCCA cell lines using RT-qPCR and Western blot. EIF3H has been identified as a critical molecule that plays a pro-neoplasmic role in iCCA both in vivo and in vitro, such as proliferation, migration, and anti-apoptosis. Mechanistically, we found that EIF3H knockdown can promote the degradation of CCND1 and the proteolysis of CCND1 is mediated by ubiquitin-proteasome system (UPS). Thus, we come to the conclusion that EIF3H promotes proliferation and migration of iCCAs, inhibiting apoptosis of iCCA cells at the same time by stabilizing the CCND1 protein structure. Our findings provide insights into the mechanism of tumorigenesis role of EIF3H in iCCAs and a potential therapeutic target for iCCA treatment.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , beta Catenina , Ciclina D1/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia
17.
Front Immunol ; 13: 982196, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341387

RESUMO

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy and carries a dismal prognosis due to difficulties in achieving an optimal resection, and poor response to current standard-of-care systemic therapies. We previously devised a CTLA4-PD-L1 DNA cancer vaccine (DNA vaccine) and demonstrated its therapeutic effects on reducing tumor growth in a thioacetamide (TAA)-induced rat intrahepatic CCA (iCCA) model. Here, we developed a CTLA4-PD-L1 chimeric protein vaccine (Protein vaccine), and examined its effects in the rat iCCA model. In a therapeutic setting, iCCA-bearing rats received either DNA plus Protein vaccines or Protein vaccine alone, resulting in increased PD-L1 and CTLA-4 antibody titers, and reduced iCCA tumor burden as verified by animal positron emission tomography (PET) scans. Treating iCCA-bearing rats with Protein vaccine alone led to the increase of CTAL4 antibody titers that correlated with the decrease of tumor SUV ratio, indicating regressed tumor burden, along with increased <i>CD8</i> and granzyme A (<i>GZMA</i>) expression, and decreased PD-L1 expression on tumor cells. In a preventive setting, DNA or Protein vaccines were injected in rats before the induction of iCCA by TAA. Protein vaccines induced a more sustained PD-L1 and CTLA-4 antibody titers compared with DNA vaccines, and was more potent in preventing iCCA tumorigenesis. Correspondingly, Protein vaccines, but not DNA vaccines, downregulated PD-L1 gene expression and hindered the carcinogenesis of iCCA. Taken together, the CTLA4-PD-L1 chimeric protein vaccine may function both as a therapeutic cancer vaccine and as a preventive cancer vaccine in the TAA-induced iCCA rat model.


Assuntos
Neoplasias dos Ductos Biliares , Vacinas Anticâncer , Colangiocarcinoma , Animais , Ratos , Antígeno CTLA-4/genética , Antígeno B7-H1 , Proteínas de Checkpoint Imunológico , Colangiocarcinoma/genética , Colangiocarcinoma/prevenção & controle , Colangiocarcinoma/metabolismo , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Tioacetamida , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/prevenção & controle , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Proteínas Recombinantes de Fusão
18.
Curr Opin Organ Transplant ; 27(4): 320-328, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36354258

RESUMO

PURPOSE OF REVIEW: Liver transplantation for intrahepatic cholangiocarcinoma (iCCA) has been mired in controversy. High rates of recurrence posttransplant combined with donor organ scarcity resulted in most transplant centers treating iCCA as a contraindication for liver transplantation. RECENT FINDINGS: Recent studies have shown that carefully selected patients with unresectable iCCA can have good outcomes after liver transplantation. Better outcomes have been seen in patients with smaller tumors and favorable tumor biology. SUMMARY: Because many patients are diagnosed with iCCA at later stages, tumor biology and genetics are useful tools to identify patients who will have excellent overall and recurrence-free survival after liver transplantation. Further larger multicenter prospective studies are needed to identify patients who would benefit from liver transplantation with good outcomes. Additional advances will come through early diagnosis and utilizing a combination of chemotherapy and locoregional modalities as a bridge to transplant. There is also a need to recognize and develop additional neo- and adjuvant therapies for patients whose tumor biology currently precludes their inclusion on the liver transplantation waitlist.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transplante de Fígado , Humanos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/genética , Colangiocarcinoma/cirurgia , Ductos Biliares Intra-Hepáticos/patologia , Estudos Multicêntricos como Assunto
19.
BMJ Case Rep ; 15(11)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36332934

RESUMO

Hepatobiliary tuberculosis is a rare condition causing obstructive jaundice either by enlarged lymph nodes around the bile ducts or involvement of biliary epithelium by the tuberculous process. Since a tissue diagnosis is not mandatory to proceed with the resection or initiation of a liver transplant protocol, benign lesions are occasionally misdiagnosed as hilar cholangiocarcinoma. Here, we present a case of hepatobiliary tuberculosis which presented as obstructive jaundice due to hilar obstruction. The mass causing the obstruction was then later found to be a pseudotumour, typical of tuberculosis. This diagnosis meant that extensive surgical resection as a protocol for cholangiocarcinoma was avoided. The patient recovered completely after a course of antitubercular therapy.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Icterícia Obstrutiva , Tumor de Klatskin , Tuberculose , Humanos , Tumor de Klatskin/cirurgia , Icterícia Obstrutiva/etiologia , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/cirurgia , Ductos Biliares Intra-Hepáticos/patologia
20.
Rozhl Chir ; 101(10): 478-487, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36402559

RESUMO

Cholangiocarcinoma is a relatively rare malignant tumor arising from the biliary epithelium of the intra- and extrahepatic bile ducts, the gallbladder, and the ampulla of Vater. This review article presents cholangiocarcinoma from the routine histopathological point of view. In addition to an overview of basic morphological, immunohistochemical, and molecular genetic characteristics of cholangiocarcinoma subtypes and precancerous lesions, the article is focused on intraoperative biopsies and on changes in the 8th edition of the TNM classification. Macroscopic and microscopic photo documentation and a review of recent literature are included.


Assuntos
Neoplasias dos Ductos Biliares , Ductos Biliares Extra-Hepáticos , Colangiocarcinoma , Humanos , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Patologistas , Colangiocarcinoma/patologia , Ductos Biliares Extra-Hepáticos/patologia
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