Afatinib ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoembryonic Antigen ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Gallbladder Neoplasms ; drug therapy ; pathology ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Neoplasm Staging ; Tomography, X-Ray Computed

BACKGROUNDFarnesoid X receptor (FXR) regulates tumorigenesis, but its clinical significance in gallbladder cancer (GBC) remains unclear. This study investigated its clinical and prognostic significance in GBC patients, as well as its association with the anti-apoptotic protein, myeloid cell leukemia sequence 1 (MCL1) protein.

METHODSFXR and MCL1 expression in 42 primary GBC and 15 normal gallbladder tissues were analyzed by immunohistochemistry. The patients and samples were collected from Ren Ji Hospital from January 2005 to December 2010. Their association with clinicopathologic factors and prognosis, as well as the correlation between FXR and MCL1 protein expression were analyzed by statistical analyses.

RESULTSCompared with normal gallbladder tissues, FXR expression was decreased and MCL1 expression was increased in GBC, during progression of tumor node metastasis (TNM) stage. The Kaplan-Meier survival analysis showed that FXR low-expression and MCL1 over-expression were significantly associated with overall poor survival. Furthermore, multivariate analysis showed that FXR and MCL1 are both prognostic factors for GBC patients. FXR low-expression was significantly correlated with MCL1 over-expression.

CONCLUSIONFXR might be a new molecular marker to predict the prognosis of patients with GBC and a novel therapeutic target.

Adult ; Aged ; Aged, 80 and over ; Disease Progression ; Female ; Gallbladder Neoplasms ; diagnosis ; metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Myeloid Cell Leukemia Sequence 1 Protein ; metabolism ; Neoplasm Staging ; Prognosis ; Receptors, Cytoplasmic and Nuclear ; metabolism

BACKGROUNDCurrently, all frequently used staging systems in gallbladder cancer (GBC) are based on postoperative pathological examinations. In patients undergoing curative operation, there is no effective method to predict survival preoperatively. In this study, we explored whether a combined utilization of two tumor biomarkers, namely carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), could give a preoperative prediction of survival in resectable GBC.

METHODSSeventy-three patients who underwent radical resection for GBC were included in this study. A retrospective analysis of clinical-pathological data was conducted.

RESULTSBy multivariate analysis, CA 19-9 elevation (P < 0.05) and CEA elevation (P < 0.001) were discovered as two individual factors for postoperative survival. By a combined utilization, patients were divided into three groups: patients with elevation of CEA (group I), patients with elevation of CA 19-9 but without CEA (group II), and patients with nonelevations of either CA 19-9 or CEA (group III). The cumulative 5-year survival rates in groups I, II, and III were 0, 14.0%, and 42.8%, respectively (P < 0.05).

CONCLUSIONSBy a combined utilization of CA 19-9 and CEA, individualized prediction of survival is available in resectable GBC before operation. Extended radical operation brings the most prognostic benefits in patients with nonelevations of either CA 19-9 or CEA. However, if operation would be in a larger-scale destructive manner, careful consideration of surgical decisions should be made in patients with elevation of tumor biomarkers, especially CEA.

Adult ; Aged ; Aged, 80 and over ; CA-19-9 Antigen ; metabolism ; Carcinoembryonic Antigen ; metabolism ; Female ; Gallbladder Neoplasms ; metabolism ; mortality ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Retrospective Studies

OBJECTIVETo study the relationship between the change of coagulation and the clinicopathologic characteristics in patients with gallbladder cancer.

METHODSThe 64 gallbladder cancer patients (GBC group) and 60 cholecystitis patients (control group) had been reviewed from January 2007 to June 2013. The prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), and thrombin time (TT) had been measured and compared between patients of GBC group and control group. The relationship of coagulation function and prognosis were analyzed.

RESULTSCompared with control group, APTT in GBC group ((29.0 ± 4.2) s) was significantly shortened (t = -4.265, P = 0.000) and PT ((11.5 ± 1.4) s), TT ((15.3 ± 3.5) s), Fib ((4.1 ± 0.9) g/L) were significantly increased in GBC group (t = 2.521, 4.147 and 4.365, all P < 0.05). The level of Fib was higher in patients with medium or poor-differentiated tumor cells (F = 4.069, P = 0.022), lymph metastasis (t = 2.640, P = 0.010) and advanced staging (II-IV) (t = 3.003, P < 0.01) than those of well-differentiated, non-lymph metastasis and early staging (0-I). The ratio of gallbladder cancer with hyperfibrinogenemia (32/64) was significantly higher than control group (11/60, χ(2) = 13.709, P < 0.01). In GBC group, compared with normal Fib patients, hyperfibrinogenemia patients showed significantly difference in clinicopathologic characteristics (χ(2) = 5.851-10.573, P < 0.05). The average survival period of hyperfibrinogenemia patients and normal Fib patients were 8.63 months and 16.73 months. The 1-, 3-year survival rate of patients with hyperfibrinogenemia were significantly lower than those with normal Fib (64.7%, 14.9% vs. 74.9%, 21.1%, P < 0.05).

CONCLUSIONPreoperative plasma level of Fib might be a new promising biomarker in patients with gallbladder cancer for evaluating disease progression and prognosis.

Adult ; Aged ; Aged, 80 and over ; Blood Coagulation ; Case-Control Studies ; Female ; Fibrinogen ; metabolism ; Gallbladder Neoplasms ; physiopathology ; Humans ; Male ; Middle Aged ; Prognosis ; Prothrombin Time

BACKGROUND/AIMS: Few studies have assessed the prognostic value of the primary tumor maximum standardized uptake value (SUVmax) measured by 2-[18F]-fluoro-2-deoxy-D-glucose PET-CT for patients with bile duct and gallbladder cancer. METHODS: A retrospective analysis of 61 patients with confirmed bile duct and gallbladder cancer who underwent FDG PET-CT in Kangbuk Samsung Medical Center (Seoul, Korea) from April 2008 to April 2011. Prognostic significance of SUVmax and other clinicopathological variables was assessed. RESULTS: Twenty-three patients were diagnosed as common bile duct cancer, 17 as hilar bile duct cancer, 12 as intrahepatic bile duct cancer, and nine as gallbladder cancer. In univariate analysis, diagnosis of intrahepatic cholangiocarcinoma and gallbladder cancer, mass forming type, poorly differentiated cell type, nonsurgical treatment, advanced American Joint Committee on Cancer (AJCC) staging and primary tumor SUVmax were significant predictors of poor overall survival. In multivariate analysis adjusted for age and sex, primary tumor SUVmax (hazard ratio [HR], 4.526; 95% CI, 1.813-11.299), advanced AJCC staging (HR, 4.843; 95% CI, 1.760-13.328), and nonsurgical treatment (HR, 6.029; 95% CI, 1.989-18.271) were independently associated with poor overall survival. CONCLUSIONS: Primary tumor SUVmax measured by FDG PET-CT is an independent and significant prognostic factor for overall survival in bile duct and gallbladder cancer.
Aged ; Bile Duct Neoplasms/*diagnosis/mortality/radionuclide imaging ; Cholangiocarcinoma/diagnosis/mortality/radionuclide imaging ; Female ; Fluorodeoxyglucose F18/diagnostic use/metabolism/standards ; Gallbladder Neoplasms/*diagnosis/mortality/radionuclide imaging ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/diagnosis/mortality/radionuclide imaging ; Male ; Middle Aged ; Neoplasm Staging ; Positron-Emission Tomography/standards ; Prognosis ; Proportional Hazards Models ; Radiopharmaceuticals/diagnostic use/metabolism/standards ; Retrospective Studies ; Tomography, X-Ray Computed/standards

OBJECTIVETo study the role of arginase-1 (Arg-1) expression in differential diagnosis of hepatocellular carcinoma (HCC), Arg-1 staining pattern in clear cell neoplasm (HCC and non-HCC) and Arg-1 expression in non-hepatocellular tumors.

METHODSSeventy-eight cases of HCC (including 8 cases of clear cell type and 70 cases of non- clear cell type) and 246 cases of non-hepatocellular neoplasms (including 29 cases of metastatic tumors such as breast cancer, nasopharyngeal carcinoma and neuroendocrine carcinoma, 77 cases of tumors with clear cell changes such as malignant melanoma, clear cell renal cell carcinoma and alveolar soft part sarcoma, and 140 cases of other types of tumors such as ovarian endometrioid adenocarcinoma, pituitary tumor and thyroid papillary carcinoma) were studied.Immunohistochemical study for Arg-1 was performed on the paraffin-embedded tumor tissue.

RESULTSIn HCC, Arg-1 demonstrated both cytoplasmic and nuclear staining, with an overall sensitivity of 96.2% (75/78).In well, moderately and poorly differentiated HCC, the sensitivity was 15/15, 100% (41/41) and 86.4% (19/22), respectively. That was in contrast to negative staining for Arg-1 in all the 29 cases of metastatic tumors studied. The sensitivity, specificity, positive predictive value and negative predictive value of Arg-1 in distinguishing HCC from metastatic tumors was 96.2%, 100%, 100% and 90.6%, respectively. Cytoplasmic and membranous staining was observed in clear cell type of HCC. The overall sensitivity of Arg-1 expression in the 77 cases of tumors with clear cell changes was 14.3% (11/77), including 8/15 for malignant melanoma, 2/4 for ovarian clear cell carcinoma and 1/1 gall bladder adenocarcinoma with clear cell component.In malignant melanoma and ovarian clear cell carcinoma, only cytoplasmic staining was demonstrated. There was no expression of Arg-1 in the 140 cases of other tumor types studied.

CONCLUSIONSArg-1 is a sensitive and specific marker for HCC.It is a potentially useful immunohistochemical marker in distinguishing HCC from metastatic tumors. Though also expressed in malignant melanoma and ovarian clear cell carcinoma, Arg-1 shows a different staining pattern as compared with that in HCC.

Adenocarcinoma ; enzymology ; Adult ; Aged ; Arginase ; metabolism ; Carcinoma, Hepatocellular ; enzymology ; pathology ; secondary ; Cell Differentiation ; Diagnosis, Differential ; Female ; Gallbladder Neoplasms ; enzymology ; Humans ; Liver Neoplasms ; enzymology ; pathology ; secondary ; Male ; Melanoma ; enzymology ; Middle Aged ; Ovarian Neoplasms ; enzymology ; Stomach Neoplasms ; enzymology ; pathology

OBJECTIVETo examine the expression of tissue factor pathway inhibitor-2 (TFPI-2) in gallbladder cancer (GBC) and to investigate the anti-cancer activities of TFPI-2 against the growth of GBC.

METHODSTFPI-2 expression in gallbladder normal tissues, gallbladder polyp (GBP) tissues and GBC tissues were examined by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot and immunohistochemical staining. Adenovirus carrying human TFPI-2 gene (Ad5-TFPI-2) were constructed and its anti-cancer effects were investigated in xenograft tumors. Xenograft tumors were constructed by injection of GBC-SD and SGC-996 cells into the flank of nude mice and the volume of xenograft tumors was measured every 3 days until the sacrifice of mice. The apoptosis index of xenograft tumors was examined by TUNEL assay. The status of Bax, Bcl-2 and caspase-3 was examined by Western blot assay.

RESULTSTFPI-2 expression was profoundly lower in GBC tissues (87.0%) when compared to normal tissues (23.3%) and GBP tissues (52.2%; χ(2) = 21.104, P = 0.000). Ad-TFPI-2 significantly inhibited the growth of xenograft tumors in nude mice. Ad-TFPI-2 inhibited GBC-SD cell growth through the induction of apoptosis. The means of total apoptotic cells per field were much higher in Ad5-TFPI-2 group than those in PBS and Ad5-GFP groups. Ad5-TFPI-2 elevated the expression of Bax and cleaved caspase-3, while it decreased the expression of Bcl-2.

CONCLUSIONSTFPI-2 gene and protein was down-regulated in GBC and the down-regulation of TFPI-2 may play a role in the tumorigenesis of GBC. Adenovirus-mediated TFPI-2 can inhibit GBC growth through the induction of apoptosis.

Adenoviridae ; genetics ; Aged ; Animals ; Apoptosis ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Female ; Gallbladder Neoplasms ; metabolism ; pathology ; therapy ; Genetic Therapy ; Glycoproteins ; genetics ; metabolism ; Humans ; Male ; Mice ; Mice, Nude ; Middle Aged ; Neoplasm Transplantation ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; bcl-2-Associated X Protein ; metabolism

BACKGROUNDThe precise molecular mechanisms underlying the gallbladder carcinoma (GBC) metastasis has not been fully elucidated.

METHODSIn the present study, metastasis-associated proteins were identified by comparative proteomic analysis. The functional study of the candidate protein vimentin was further investigated. First, a pair of higher and lower metastatic sublines (termed GBC-SD/M3 and GBC-SD, respectively), originated from the same parental cell line, was screened by spontaneous tumorigenicity and metastasis in vivo in animal study and further characterized by metastatic phenotypes analysis in vitro. Subsequently, a proteomic approach comprised two-dimensional gel electrophoresis analysis and mass spectroscopy was used to identify and compare the protein expression patterns between higher metastatic GBC-SD/M3 and lower metastatic GBC-SD cell lines. Then twenty-six proteins were identified.

RESULTSAmong the 26 proteins identified, fourteen proteins were up-regulated and 12 proteins were down-regulated in GBC-SD/M3. Vimentin was identified and found to be overexpressed in GBC-SD/M3 as compared with GBC-SD. This result was further confirmed by quantitative PCR and Western blotting analysis. Furthermore, the cell migration and invasion potency of GBC-SD/M3 in vitro was remarkably suppressed after small interference RNA-mediated knockdown of vimentin. Moreover, immunoblot and immunohistochemical analysis on 12 human GBC specimens showed consistently increased vimentin expression in metastases compared with primary tumors.

CONCLUSIONTumor vimentin level may reflect the pathological progression in some GBC and may be a useful marker for predicting tumor metastasis and a therapeutic target for the treatment of GBC patients with metastases.

Animals ; Blotting, Western ; Cell Line, Tumor ; Cell Movement ; genetics ; physiology ; Electrophoresis, Gel, Two-Dimensional ; Gallbladder Neoplasms ; genetics ; metabolism ; pathology ; Humans ; Immunohistochemistry ; Mice ; Mice, Nude ; Neoplasm Metastasis ; genetics ; pathology ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Vimentin ; genetics ; metabolism

Adenocarcinoma ; metabolism ; pathology ; Carcinoid Tumor ; metabolism ; pathology ; surgery ; Child ; Chromogranin A ; metabolism ; Common Bile Duct ; pathology ; surgery ; Common Bile Duct Neoplasms ; metabolism ; pathology ; surgery ; Diagnosis, Differential ; Duodenum ; pathology ; surgery ; Gallbladder ; pathology ; surgery ; Humans ; Keratins ; metabolism ; Lymphoma ; metabolism ; pathology ; Male ; Mucin-1 ; metabolism ; Neoplasm Invasiveness ; Rhabdomyosarcoma ; metabolism ; pathology ; Stomach ; pathology ; surgery ; Synaptophysin ; metabolism

OBJECTIVETo study the expression of ephrin-A7 (EphA7) and metadherin (MTDH) and their clinicopathological significances in the benign and malignant lesions of gallbladder.

METHODSEnVisiom immunohistochemical methods was used for determining the expressions of EphA7 and MTDH in routinely paraffin-embedded sections of surgically-resected specimens from 108 cases with gallbladder adenocarcinoma, 15 cases with adenomatous polyp and 35 cases with chronic cholecystitis treated from June 1996 to June 2006. And 46 cases of peritumoral tissues were also harvested as controls (n = 35).

RESULTSThe positive expression rates of EphA7 and MTDH were significantly higher in gallbladder adenocarcinoma than those in peritumoral tissues (χ(2)(EphA7) = 12.65, χ(2)(MTDH) = 13.00; P < 0.01), adenomatous polyp (χ(2)(EphA7) = 8.21, χ(2)(MTDH) = 9.39; P < 0.01) and chronic cholecystitis (χ(2)(EphA7) = 21.21, χ(2)(MTDH) = 23.68; P < 0.01); Moderately-or severely-atypical hyperplasia of gallbladder epithelium was found in the benign lesions with positive expression of EphA7 and/or MTDH. The positive rates of EphA7 and MTDH were significantly lower in the cases of well-differentiated adenocarcinoma, maximal diameter of tumor < 2 cm, no-metastasis of lymph node, and tumor with no-invasiveness of regional tissues than those in the poorly-differentiated adenocarcinoma (χ(2)(EphA7) = 12.34, χ(2)(MTDH) = 12.80; P < 0.01), maximal diameter of tumor ≥ 2 cm (χ(2)(EphA7) = 5.22, χ(2)(MTDH) = 5.00; P < 0.05), cases with metastasis of lymph node (χ(2)(EphA7) = 5.15, χ(2)(MTDH) = 5.86; P < 0.05) and cases with invasiveness of regional tissues (χ(2)(EphA7) = 7.06, P < 0.01; χ(2)(MTDH) = 4.13; P < 0.05) in gallbladder adenocarcinoma (P < 0.05). The high consistency was found between the expressive levels of EphA7 and MTDH in gallbladder adenocarcinoma (χ(2) = 13.11, P < 0.01). The univariate Kaplan-Meier analysis showed that the increased expression of EphA7 (P = 0.023) and MTDH (P = 0.034) was negatively associated with the overall survival. The multivariate Cox regression analysis showed that increased expression of EphA7 and/or MTDH (P(EphA2) = 0.023, P(MTDH) = 0.034) was an independent poor-prognostic predictor for gallbladder adenocarcinoma.

CONCLUSIONSThe expression of EphA7 and/or MTDH might be closely related to the carcinogenesis, progression, clinical biological behaviors and prognosis of gallbladder adenocarcinoma. The positive expression of EphA7 and/or MTDH may predict bad-prognosis in gallbladder adenocarcinoma.

Adult ; Aged ; Cell Adhesion Molecules ; metabolism ; Cholecystitis ; metabolism ; pathology ; Female ; Follow-Up Studies ; Gallbladder ; metabolism ; pathology ; Gallbladder Diseases ; metabolism ; pathology ; Gallbladder Neoplasms ; metabolism ; pathology ; Humans ; Male ; Middle Aged ; Polyps ; metabolism ; pathology ; Prognosis ; Receptor, EphA7 ; metabolism