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1.
PLoS One ; 15(12): e0240791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33306714

RESUMO

OBJECTIVES: Although elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with survival in some liver cancers, its prognostic relevance has not been studied in the context of combined hepatocellular cholangiocarcinoma CHCC-CC, a rare primary liver cancer. We investigated whether elevated NLR and a predominance of cholangiocarcinoma might predict poor prognosis in patients with resectable CHCC-CC. METHODS: We retrospectively reviewed the clinicopathologic data of forty-two patients with CHCC-CC receiving hepatectomies at our hospital. We used Kaplan-Meier and Cox regression to analyze survival. RESULTS: Two-year disease-free survival and five-year overall survival rates were 43.2% and 32.9%, respectively. Univariate analyses showed that patients with NLR ≥3 had significantly worse 2-year DFS and 5-year OS rates. Univariant Kaplan-Meier survival analysis also associated these rates with a predominance in intrahepatic cholangiocarcinoma, AJCC tumor stage, pathological T stage and lymph-vascular invasion. However, our multivariate analysis found NLR ≥3 to be the only independent predictor of disease recurrence and poorer survival. CONCLUSIONS: Neutrophil-to-lymphocyte ratio was the most important independent predictor of poorer survival in patients with resectable CHCC-CC. Predominance of intrahepatic cholangiocarcinoma, advanced AJCC tumor stage and pathological T stage, and lymph-vascular invasion also may affect poor prognosis in patients receiving complete tumor resections.


Assuntos
Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/sangue , Colangiocarcinoma/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , Carcinoma Hepatocelular/cirurgia , Colangiocarcinoma/cirurgia , Feminino , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias Complexas Mistas/sangue , Neoplasias Complexas Mistas/patologia , Neoplasias Complexas Mistas/cirurgia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
2.
Life Sci ; 262: 118548, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038372

RESUMO

AIMS: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness. MAIN METHODS: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence. KEY FINDINGS: Data indicated that high glucose increased the expression of interleukin-1ß (IL-1ß), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705. SIGNIFICANCE: These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Humanos , Interleucina-1beta/genética , Invasividade Neoplásica
3.
Cancer Genet ; 248-249: 57-62, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33093002

RESUMO

BRCA1 associated protein-1 (BAP1) germline mutations define a novel hereditary cancer syndrome, namely BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by an increased susceptibility to develop different cancer types, including mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and basal cell and squamous cell carcinoma. Currently, the role of BAP1 germline mutations in intrahepatic cholangiocarcinoma (iCCA) pathogenesis is less known. Here we report the first clinical case of a female patient who developed an iCCA when she was 47-years-old and was found to carry a novel germline mutation at a splicing site of exon 4 in BAP1 gene (NM_004656.4: c.255_255+6del). An accurate anamnesis revealed the absence of risk factors linked to iCCA development, except for a low occupational exposure to asbestos. In tumor tissue, BAP1 sequencing, multiplex ligation-dependent probe amplification and immunoistochemistry showed the loss of heterozygosity and lack of nuclear expression, suggesting that BAP1 wild-type allele and functional protein were lost in cancer cells, in line with the classical two-hit model of tumor suppressor genes. Further studies are needed to confirm whether iCCA may be included into BAP1-TPDS cancer phenotypes and whether minimal asbestos exposure may facilitate the development of this malignancy in individuals carrying BAP1 germline mutations.


Assuntos
Asbestos/efeitos adversos , Neoplasias dos Ductos Biliares/patologia , Carcinógenos , Colangiocarcinoma/patologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
4.
J Cancer Res Ther ; 16(5): 1119-1124, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33004757

RESUMO

Objective: We sought to analyze the efficacy and safety of preserving the Oddis sphincter during metallic biliary stent implantation in patients with malignant obstructive jaundice. Materials and Methods: In a retrospective analysis, 133 patients with malignant obstructive jaundice who were admitted to our hospital from January 2010 to January 2017 and who underwent metallic biliary stent implantation were divided into two groups - the Oddis sphincter retention group (n = 55) and the Oddis sphincter nonretention group (n = 78) - according to whether the Oddis sphincter was left untouched during stent placement. The patient clinical data as well as information on complications, time of stent patency, improvement in liver function, and decline of serum bilirubin were reviewed and evaluated. Statistical analysis was performed using the Statistical Package for the Social Sciences version 19.0 (IBM Corp., Armonk, NY, USA, USA) and Prism version 7 (GraphPad Software, San Diego, CA, USA). Results: The median follow-up time was 9.6 months (range: 1-20 months) and there was no significant difference in general clinical information between the two groups. However, the incidence rates of acute biliary infection, recurrent biliary infection, acute pancreatitis, chronic pancreatitis, and asymptomatic pancreatic enzyme levels were higher in the Oddis sphincter retention group and the differences were all statistically significant (P < 0.05). Conversely, there were no significant differences in bilirubin decline, liver function improvement, and stent patency between the two groups (P > 0.05). Conclusion: Leaving the Oddis sphincter untouched during biliary stent placement can reduce the incidence of postoperative complications, while there was no effect on stent patency or jaundice relief. Therefore, it is recommended to preserve the Oddis sphincter when the stenosis is more than 3 cm above the duodenal papilla.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Icterícia Obstrutiva/cirurgia , Testes de Função Hepática/métodos , Metais/química , Próteses e Implantes , Esfíncter da Ampola Hepatopancreática/cirurgia , Stents/estatística & dados numéricos , Adulto , Idoso , Neoplasias dos Ductos Biliares/patologia , Feminino , Humanos , Icterícia Obstrutiva/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Esfíncter da Ampola Hepatopancreática/patologia , Resultado do Tratamento
5.
Medicine (Baltimore) ; 99(35): e20932, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871859

RESUMO

BACKGROUND: Accurate clinical staging of patients with cholangiocarcinoma (CCA) has a significant impact on treatment decisions. In this study, we aimed to compare the diagnostic value of magnetic resonance imaging (MRI) and 18-fludeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) for staging of CCA. METHODS: We performed comprehensive systematic search in Web of Science (including MEDLINE) and Excerpta Medica Database for relevant diagnostic studies in accordance with the preferred reporting items for systematic reviews and meta-analysis statement. Based on data extracted from patient-based analysis, we calculated the pooled sensitivity and specificity with the 95% confidence intervals (CIs). In addition, the publication bias was assessed by Deek funnel plot of the asymmetry test. The potential heterogeneity was explored by threshold effect analysis and subgroup analyses. RESULTS: Thirty-two studies with 1626 patients were included in present analysis. In T stage, the pooled sensitivity and specificity of MRI were 0.90 (95% CI 0.86-0.93), 0.84 (95% CI 0.73-0.91) respectively. The pooled sensitivity and specificity of F-FDG PET/CT were 0.91 (95% CI 0.83-0.95) and 0.85 (0.64-0.95) respectively. In N stage, the pooled sensitivity and specificity of MRI were 0.64 (95% CI 0.52-0.74) and 0.69 (95% CI 0.51-0.87) respectively. The pooled sensitivity and specificity of PET/CT were 0.52 (95% CI 0.37-0.66) and 0.92 (95% CI 0.79-0.97) respectively. In M stage, the pooled sensitivity and specificity of F-FDG PET/CT were 0.56 (95% CI, 0.42-0.69) and 0.95 (95% CI, 0.91-0.97) respectively. The Deek test revealed no significant publication bias. No threshold effect was identified. The subgroup analyses showed that pathological type (extrahepatic cholangiocarcinoma vs hilar cholangiocarcinoma/intrahepatic cholangiocarcinoma), country (Asia vs non-Asia) and type of MRI (1.5T vs. 3.0T) were potential causes for the heterogeneity of MRI studies and country (Asia vs non-Asia) was a potential source for F-FDG PET/CT studies. CONCLUSION: The analysis suggested that both modalities provide reasonable diagnostic accuracy in T stage without significant differences between them. We recommend that both modalities be considered based on local availability and practice for the diagnosis of primary CCA tumors. In N stage, the diagnosis of lymph node metastasis (N) of CCA is still limited by MRI and F-FDG PET/CT, due to unsatisfactory diagnostic accuracy of both. Nevertheless, F-FDG PET/CT can be used to confirm lymph node metastasis while a negative result may not rule out metastasis. Furthermore, F-FDG PET/CT have a low sensitivity and a high specificity for detection of distant metastasis.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Idoso , Colangiocarcinoma/epidemiologia , Feminino , Fluordesoxiglucose F18/administração & dosagem , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Estadiamento de Neoplasias/métodos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodos
6.
Medicine (Baltimore) ; 99(38): e22255, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957374

RESUMO

The expression of Cystathionine beta-synthase (CBS) and Chemokine ligand 21 (CCL21) is associated with the tumorigenesis and progression of a variety of tumors, but whether alterations in their expression levels correlates with the carcinogenesis and progression of EHCC is still unknown. This study investigated the clinicopathological significance of CBS and CCL21 expression in EHCC.We investigated the correlations between the expression of CBS and CCL21 and clinicopathological characteristics in EHCC using EnVision immunohistochemistry.The expression of CBS and CCL21 was significantly higher in EHCC tumors than in nontumor tissues (P < .05 and P < .01). EHCC patients with CBS and CCL21 expression combined with lymph node metastasis, tumor cell invasion, and TNM III/IV stage had more severe conditions than those with no lymph node metastasis, distant invasion and TNM I/II stage (P < .01). Kaplan-Meier survival analysis showed that the overall survival rates for EHCC patients with negative CBS or CCL21 reaction were significantly higher than those for patients with positive CBS or CCL21 reaction((P < .01). CBS or CCL21 expression was revealed as an independent poor prognostic factor for EHCC patients by Cox multivariate analysis.The present study indicates that CBS and CCL21 expression is closely associated with the pathogenesis of clinical, pathological and biological behaviors and poor prognosis in EHCC.


Assuntos
Neoplasias dos Ductos Biliares/genética , Quimiocina CCL21/genética , Colangiocarcinoma/genética , Cistationina beta-Sintase/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico
7.
J Surg Oncol ; 122(8): 1580-1586, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32895951

RESUMO

OBJECTIVE: The aim of this study was to present a novel bile-duct obstructed area imaging (BOAI) and to investigate the feasibility and accuracy of this method in guiding hepatectomy for intrahepatic cholangiocarcinoma (ICC) with intrahepatic biliary obstruction. METHODS: From May 2017 to October 2019, eligible patients who underwent hepatectomy guided by BOAI were enrolled. Perioperative outcomes and operative data were analyzed. To assess the feasibility of BOAI and Glissonean pedicle approach, demarcations based on them were compared. To verify the accuracy of BOAI staining of the target territory, simple linear regression analysis, and intraclass correlation coefficient were used to examine the relationship between predicted resected liver volume (PRLV) and actual resected liver volume (ARLV). RESULTS: BOAI staining achieved valid demarcation in 15 (93.8%) of 16 patients, whereas the ischemic line achieved valid demarcation in only nine patients (57.3%; p = .017). ARLV and PRLV had a strong positive correlation (PRLV = 60.06 + 0.925 × ARLV; R = .945; p = .000). Meanwhile, ARLV (intraclass correlation coefficient = .971) achieved an excellent agreement with PRLV (p < .001). CONCLUSIONS: The novel BOAI staining method can provide valid, feasible, and accurate demarcation line and may be an effective method in the surgical treatment of intrahepatic biliary obstruction.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Colestase/cirurgia , Corantes/química , Diagnóstico por Imagem/métodos , Hepatectomia/métodos , Cirurgia Assistida por Computador/métodos , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Colestase/diagnóstico por imagem , Colestase/patologia , Estudos de Viabilidade , Feminino , Fluorescência , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
8.
Int J Clin Oncol ; 25(12): 2083-2089, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32869120

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (IHCC) has a poor prognosis, and surgery remains the only effective treatment. However, tumor recurrence after primary hepatectomy is common. We examined the significance of repeat surgery for IHCC. METHODS: We collected data for all patients with IHCC between 1992 and 2018 (n = 67) in our database. Fifty-three (79.1%) of all 67 patients experienced recurrence after primary hepatectomy and we analyzed data for those 53 recurrent patients. We divided recurrent patients into a repeat surgery group (n = 9), chemotherapy group (n = 19), and best supportive care group (n = 25). We analyzed differences in patients' clinicopathological factors, including prognosis, between the three groups. RESULTS: The IHCC recurrence rate after hepatectomy in our institution was 79.1%. Of the 53 patients with recurrence, nine underwent repeat surgery (17.0%). The characteristics of the patients undergoing repeat surgery was lower stage at primary hepatectomy. Recurrence sites in the repeat surgery group were liver (n = 6), lung (n = 2), and adrenal gland (n = 1), as a single nodule. The period between primary hepatectomy and recurrence was comparatively longer in the repeat surgery group, at 1.8 years. The prognosis in patients undergoing repeat surgery was significantly better compared with the other groups. Not undergoing repeat surgery (hazard ratio: 5.506; p = 0.0077) and positive lymph node metastasis (hazard ratio: 2.207; p = 0.0242) were independent poor prognostic factors. CONCLUSIONS: Repeat surgery should be considered in patients with IHCC with a single recurrence site and negative lymph node metastasis at primary surgery and at least more than 6 months of disease-free period after primary surgery.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/cirurgia , Hepatectomia/métodos , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Modelos de Riscos Proporcionais , Reoperação , Resultado do Tratamento
9.
Anticancer Res ; 40(9): 5115-5124, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878800

RESUMO

BACKGROUND/AIM: Pyruvate kinase M2 (PKM2) is an enzyme that is predominantly overexpressed in various types of cancer. The role of PKM2 in liver fluke-associated cholangiocarcinoma (CCA) remains unclear. This study aimed to investigate the antitumor activity of shikonin, a PKM2 inhibitor, in CCA cells. MATERIALS AND METHODS: Immunohistochemistry and immunoblotting were used to determine PKM2 expression in CCA tissues and cells. Antiproliferative effects of shikonin were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation and trypan blue exclusion assays. The anti-metastatic activity of shikonin was determined using the Boyden chamber assay. Mechanisms by which shikonin inhibited CCA progression were determined. RESULTS: PKM2 was overexpressed in CCA compared to normal bile duct epithelial cells. Shikonin significantly inhibited growth, and migration of CCA cells while inducing their death. A mechanistic study revealed that antitumor effects of shikonin in CCA cells depended on increased production of reactive oxygen species. CONCLUSION: Shikonin may be a novel therapeutic agent for patients with CCA.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Colangiocarcinoma/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Hormônios Tireóideos
10.
Am J Chin Med ; 48(6): 1475-1489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907364

RESUMO

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Quinase Piruvato Desidrogenase (Transferência de Acetil)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triterpenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias dos Ductos Biliares/dietoterapia , Linhagem Celular Tumoral , Colangiocarcinoma/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Triterpenos/uso terapêutico
11.
PLoS One ; 15(9): e0238392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881910

RESUMO

BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) has been poor, because of the high recurrence rate even after curative surgery. This study aimed to evaluate the prognostic impact of surgical resection of recurrent ICC. PATIENTS AND METHODS: A total of 345 cases of ICC who underwent hepatectomy with curative intent in 17 institutions were retrospectively analyzed, focusing on recurrence patterns and treatment modalities for recurrent ICC. RESULTS: Median survival time and overall 5-year recurrence-free survival rate were 17.8 months and 28.5%, respectively. Recurrences (n = 223) were classified as early (recurrence at ≤1 year, n = 131) or late (recurrence at >1 year, n = 92). Median survival time was poorer for early recurrence (16.3 months) than for late recurrence (47.7 months, p<0.0001). Treatment modalities for recurrence comprised surgical resection (n = 28), non-surgical treatment (n = 134), and best supportive care (BSC) (n = 61). Median and overall 1-/5-year survival rates after recurrence were 39.5 months and 84.6%/36.3% for surgical resection, 14.3 months and 62.5%/2.9% for non-surgical treatment, and 3 months and 4.8%/0% for BSC, respectively (p<0.0001). Multivariate analysis identified early recurrence, simultaneous intra- and extrahepatic recurrence, and surgical resection of recurrence as significant prognostic factors. In subgroup analyses, surgical resection may have positive prognostic impacts on intra- and extrahepatic recurrences, and even on early recurrence. However, simultaneous intra- and extrahepatic recurrence may not see any survival benefit from surgical management. CONCLUSION: Surgical resection of recurrent ICC could improve survival after recurrence, especially for patients with intra- or extrahepatic recurrence as resectable oligo-metastases.


Assuntos
Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Hepatectomia/mortalidade , Idoso , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Hepatectomia/métodos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
12.
Sci Rep ; 10(1): 15820, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978444

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is a rare but fatal tumor. The isocitrate dehydrogenase 1 and 2 (IDH1/2) genes are known to be mutated in ICC. IDH1/2 mutations tend to be accompanied by enhanced hypermethylation at a subset of genomic loci. We sought to clarify the clinicopathological features, including prognostic value, of ICCs with IDH1/2 mutation-associated hypermethylation at a subset of genes. The mutation status of IDH1/2 and methylation status of 30 gene CpG island loci were analyzed in 172 cases of ICC using pyrosequencing and the MethyLight assay, respectively. The mutation status of IDH1/2 was correlated with clinicopathological features and the DNA methylation status at 30 gene loci. Then, the clinicopathological characteristics were analyzed regarding three-tiered methylation statuses in genes showing IDH1/2 mutation-associated methylation. IDH1/2 mutations were found in 9.3% of ICCs, and IDH1/2-mutated tumors were associated with the histological subtype, including the bile ductular type and small duct type, and poor differentiation. Eight DNA methylation markers showed associations with IDH1/2 mutations, and ICCs with > 5/8 methylated markers were associated with the bile ductular type or small duct type, absence of mucin production, absence of biliary intraepithelial neoplasia, and presence of chronic liver disease. > 5/8 methylated markers were an independent prognostic marker associated with better survival in both cancer-specific survival and recurrence-free survival. In summary, by analyzing the association between IDH1/2 mutations and DNA methylation in individual genes, we developed a panel of DNA methylation markers that were significantly associated with IDH1/2 mutations and were able to identify a subset of ICC with better clinical outcomes.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Colangiocarcinoma/patologia , Metilação de DNA , Isocitrato Desidrogenase/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/genética , Colangiocarcinoma/cirurgia , Ilhas de CpG , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
13.
Biochim Biophys Acta Gen Subj ; 1864(12): 129708, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32810561

RESUMO

BACKGROUND: Ursolic acid (UA) is a natural triterpenoid which possesses anti-cancer activity. However, little is known regarding the activity and molecular mechanism of UA in cholangiocarcinoma (CCA). Thus, we investigated the effects of UA on growth inhibition and apoptosis induction through biomolecular changes in KKU-213 and KKU-055 CCA cell lines. METHODS: The anti-proliferative effect of UA against CCA cells was evaluated using SRB assay. Changes in biomolecules were assessed by SR-FTIR microspectroscopy combined with PCA and conventional methods (i.e., Annexin V-FITC/PI staining for lipid alteration and apoptosis induction; Western blot analysis and caspase-3/7 activity assay for apoptotic protein detection). RESULTS: UA suppressed the proliferation of CCA cells in a dose- and time-dependent manner. SR-FTIR data revealed a significant alteration in lipids attributable to changes in apoptotic cell membranes, confirmed by Annexin V-FITC/PI staining. SR-FTIR data showed that UA promoted changes in the protein secondary structure. Elevated expression of Bax and decreased expression of Bcl-2 and survivin/BIRC5 along with augmented caspase-3/7 activity supported alterations in apoptosis-related proteins. CONCLUSIONS: SR-FTIR microspectroscopy was successfully used as a label-free technique to monitor apoptosis-induced biomolecular changes in UA-treated CCA cells. UA exerted the cytotoxic and apoptotic activities in CCA cells through alterations in membrane lipids and apoptotic proteins. UA could be a potential anti-CCA candidate and a chemical starting point for the discovery of novel anti-cancer agents. SIGNIFICANCE: Our present study showed the first evidence that UA exhibited the anti-proliferative and pro-apoptotic activities toward CCA cells through changes in biomolecules, notably lipids and proteins.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Triterpenos/farmacologia , Neoplasias dos Ductos Biliares/química , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/química , Colangiocarcinoma/patologia , Humanos , Espectroscopia de Infravermelho com Transformada de Fourier/instrumentação , Síncrotrons/instrumentação
14.
J Med Life ; 13(2): 265-268, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742524

RESUMO

Bone metastases in cholangiocarcinoma are uncommon. We report the case of a patient with disseminated osteolytic lesions who was admitted to the Neurology Department for progressive paraparesis. On the computed tomography examination, specific features for cholangiocarcinoma were described, confirmed later by the histopathological aspect of the bone lesions.


Assuntos
Neoplasias dos Ductos Biliares/complicações , Colangiocarcinoma/complicações , Osteólise/complicações , Paraparesia/complicações , Neoplasias dos Ductos Biliares/patologia , Neoplasias Ósseas/secundário , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Colangiocarcinoma/patologia , Humanos , Masculino , Osteólise/diagnóstico por imagem , Paraparesia/diagnóstico por imagem , Tomografia Computadorizada por Raios X
15.
Clin Nucl Med ; 45(10): 798-799, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32804763

RESUMO

Biliary papillomatosis is a rare disease with high malignant potential. A 64-year-old woman underwent FDG PET/CT, which showed an intense FDG uptake in the location of an aggregated biliary papillomatosis with high-grade intraepithelial neoplasia/carcinoma in situ but did not show FDG uptake in the sporadic, small biliary papilloma. FDG PET/CT may be an effective method to identify the components of the malignant transformation of biliary papillomatosis.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Fluordesoxiglucose F18 , Papiloma/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias dos Ductos Biliares/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Papiloma/patologia
16.
PLoS One ; 15(8): e0238251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845921

RESUMO

Although mass spectrometry-based plasma proteomics enables sensitive and large-scale discovery and validation of biomarkers for various diseases, its integrative application to hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is not well investigated. Therefore, we analyzed albumin- and immunoglobulin G-depleted plasma samples from 148 and 60 patients with HCC and CCA, respectively, using liquid chromatography-tandem mass spectrometry. The algorithm used to measure the content of each protein was the percentage of exponentially modified protein abundance index. From 5320 proteins assayed in plasma, 53 and 25 biomarker candidates were identified for HCC and CCA, respectively. The abundance of six and two HCC markers particularly protruded in stage II and III, respectively, whereas plasma serine protease inhibitor was the sole marker the level of which steadily decreased with CCA progression. From a prognostic facet, we showed candidate markers and their cutoff levels for evaluating probability of tumor recurrence and patient survival period. Combination Kaplan-Meier models showed that HCC stage III or IV and both the content of alpha-2-HS-glycoprotein and apolipoprotein CIII <0.2% exhibited the poorest post-surgical recurrence-free and overall survivals. Furthermore, the content of afamin ≥0.2% played a significant role on the poor prognosis in patients with CCA. Our findings, taken together, characterized novel plasma biomarker signatures in dissecting tumor stages and post-surgical outcomes of HCC and CCA.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína C-III/sangue , Ductos Biliares Intra-Hepáticos/patologia , Proteínas de Transporte/sangue , Feminino , Glicoproteínas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Proteoma/análise , Inibidores de Serino Proteinase/sangue , Albumina Sérica Humana , alfa-2-Glicoproteína-HS/análise
17.
Am J Clin Oncol ; 43(11): 784-787, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32826390

RESUMO

OBJECTIVES: The objective of this study was to compare the clinical effectiveness of uncovered stent and covered stent as percutaneous endoprosthesis for malignant biliary obstruction of the extrahepatic bile duct. MATERIALS AND METHODS: After completion of percutaneous internal and external tube placement for unresectable malignant biliary obstruction, 60 patients were registered and randomly assigned in a 1:1 ratio to an uncovered or covered stent group. Metallic stent placement was performed within 1 week after registration, and an external biliary drainage tube was removed >3 days after stent placement. The primary endpoint was the obstructive jaundice-free survival rate at 24 weeks after registration, and the secondary endpoints were the success rate of percutaneous tube removal and adverse events. RESULTS: The obstructive jaundice-free survival rate at 24 weeks after registration was 13/29 (44.8%, 95% confidence interval [CI]: 28.4%-62.5%) and 15/30 (50.0%, 95% CI: 33.2%-66.8%) in the uncovered and covered stent groups, respectively. The success rate of percutaneous tube removal was 28/29 (96.6%, 95% CI: 82.8%-99.4%) and 30/30 (100%, 95% CI: 90.5%-100%) in the uncovered and covered stent groups, respectively. There were no procedure-related deaths. Twenty-eight adverse events were observed in 21 patients (7 in the uncovered stent group and 14 in the covered stent group). CONCLUSIONS: There was no significant difference in the obstructive jaundice-free survival rate at 24 weeks between the 2 groups. Considering the technical difficulty and invasiveness of covered stent placement, the placement of covered stents may not be needed in patients with a short prognosis of <24 weeks.


Assuntos
Neoplasias dos Ductos Biliares/complicações , Ductos Biliares Extra-Hepáticos/patologia , Ductos Biliares Extra-Hepáticos/cirurgia , Colestase/cirurgia , Stents , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Colestase/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Resultado do Tratamento
18.
Sci Rep ; 10(1): 12348, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704067

RESUMO

Pembrolizumab appears promising for patients with programmed cell death ligand-1 (PD-L1)-positive solid tumors. However, data on immunotherapy for biliary tract cancers (BTC) are limited. We aimed to investigate the predictive value of PD-L1 expression as an immunotherapeutic biomarker in BTC. Patients with advanced BTC (n = 175) were screened for PD-L1 expression using PharmDx assay and microsatellite instability (MSI) status. Of the total of 175 patients, 125 (71%) showed tumoral PD-L1 positivity (≥ 1%) while only two (2/142, 1.4%) showed MSI-High. Among 175 patients, 26 patients were treated with pembrolizumab as a second-line therapy, and tumor response was evaluated. Separating these patients into two groups by PD-L1 expression (high [≥ 50%] vs. low [< 50%]), overall response rate was 23% (56% [5/9] in high PD-L1 group vs. 6% [1/17] in low PD-L1 group, P = 0.004). Disease control rate was also higher in high PD-L1 group (78% vs. 35%, P = 0.019). The six responders showed median progression-free survival of 5.8 months after starting pembrolizumab, and none of them was MSI-High. High PD-L1 expression was associated with a better response to pembrolizumab. PD-L1 expression can potentially serve as an alternative predictive biomarker for pembrolizumab therapy in advanced BTC.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/biossíntese , Neoplasias dos Ductos Biliares , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
19.
Anticancer Res ; 40(8): 4749-4754, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727801

RESUMO

BACKGROUND/AIM: The purpose of this study was to clarify the relationship between the desmoplastic reaction (DR) and clinicopathological features, and the prognosis using cases of resected intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Out of 54 cases that were preoperatively diagnosed with ICC and underwent resection at our department, 47 patients were included in this study. All sections were prepared from resected specimens and were microscopically observed following H&E staining. Stroma were evaluated at the advancing edge of the cancer and stratified into three DR types: mature (DR1), intermediate (DR2), and immature (DR3). RESULTS: DR was correlated to the serum levels of CA19-9, but not to the other tumor factors. In multivariate analysis, only DR and tumor size were determined as independent prognostic factors. CONCLUSION: Evaluation of DR for ICC may be useful for prognostic assessments.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Biomarcadores Tumorais/metabolismo , Antígeno CA-19-9/metabolismo , Colangiocarcinoma/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
20.
Life Sci ; 257: 118068, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32653521

RESUMO

AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumour with increasing incidence and high mortality. Liver kinase B1 (LKB1) regulates cellular energy metabolism and cell division and affects immune microenvironment. This study aimed to uncover the underlying function and mechanism of LKB1 in ICC. MAIN METHODS: To determine the correlation between LKB1 levels and clinicopathological features, the expression profile of LKB1 in ICC tissue specimens was examined by qRT-PCR and western blotting. In vitro experiments were conducted to examine the anticancer effect of LKB1 in ICC. Changes in the expression of epithelial-mesenchymal transition (EMT)-associated markers and immune checkpoints were analysed by qRT-PCR, western blotting, immunofluorescence and flow cytometry. The influence of LKB1 on the transcriptional activity of PD-L1 was determined by dual-luciferase reporter assays and IFNγ induction. KEY FINDINGS: LKB1 was expressed at low levels in ICC and tightly associated with poor prognosis. LKB1 knockdown promoted the proliferation, migration, matrix adhesion and EMT of ICC cells. Notably, LKB1 silencing upregulated the surface expression of PD-L1 in ICC cells. Suppressed and mutated LKB1 enhanced the transcriptional activity of PD-L1 in ICC cells, leading to high expression of the immune checkpoint PD-L1. Furthermore, inhibiting LKB1 suppressed ICC cell apoptosis induced by IFNγ. SIGNIFICANCE: By suppressing malignant transformation and the immune checkpoint PD-L1 of cancer cells, LKB1 plays an important role in inhibiting ICC and is a potential target for clinical diagnosis and treatment. This study may provide new strategies for improving the efficiency of cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Colangiocarcinoma/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Regulação para Cima
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