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The pathologic characteristics of squamous cell/adenosquamous carcinomas (SC/ASC) have not been well clarified. As a rare subtype of gallbladder cancer (GBC), no biological markers for diagnosis and prognosis are available. This research evaluated the expression of FOXP1 and FOXO3a in 69 SC/ASC, and 146 adenocarcinoma (AC) samples were analyzed via immunohistochemistry. SC/ASCs were associated with higher rates of lymph node metastasis, invasion, and patients older than 45 years comparing to ACs. FOXP1 and FOXO3a positivity rates were significantly lower in SC/ASC and AC samples from patients with large tumor size, a high TNM stage, lymph node metastasis, invasion, and no history of tumor resection (biopsy only). Positive FOXP1 expression levels were significantly decreased in cases of poorly differentiated AC. The univariate Kaplan-Meier analysis revealed that negative FOXP1 and FOXO3a expression, poor differentiation, large tumor size, high TNM stage, lymph node metastasis, invasion, and an inability to undergo curative resection were all closely associated with decreased overall survival in SC/ASC and AC patients. The multivariate cox regression analysis showed that negative FOXP1 and FOXO3a expression levels were independent predictors of poor prognosis in SC/ASC and AC patients. Our results indicate that negative FOXP1 and FOXO3a expression are closely associated with the pathogenesis, clinicopathologic properties, and prognosis of GBC patients. FOXP1 and FOXO3a may thus be biomarkers of GBC carcinogenesis, progression, and prognosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Squamous cell/adenosquamous carcinoma (SC/ASC) is a rarely identified form of gallbladder cancer with poorly understood clinical features. As such, there is an urgent need to identify novel prognostic biomarkers for such gallbladder SC/ASC cases, and for gallbladder adenocarcinomas (ACs)., Methods: The levels of ACO2 and ANPEP proteins were assessed via an EnVision-based immunohistochemical approach using 46 SC/ASC and 80 AC patient samples., Results: There was a marked reduction in levels of ACO2 and ANPEP in gallbladder AC relative to normal adjacent tissue or benign gallbladder lesions. The was a significant correlation between lack of ACO2 and ANPEP and larger tumors, higher tumor-node-metastasis (TNM) staging, invasion, metastasis to regional lymph nodes, and ineligibility for surgical resection in both SC/ASC and AC tumor samples. Kaplan-Meier survival analyses further confirmed a relationship between ACO2 and ANPEP negativity and decreased overall survival in patients with these diseases (p < 0.05 or p < 0.01), and a multivariate regression analysis further established that ACO2 negativity and ANPEP negativity were independently predictive of poor SC/ASC and AC patient outcomes., Conclusions: ACO2 and ANPEP may have key physiological relevance in cancers of the gallbladder and thus warrant investigation as prognostic biomarkers.

Gallbladder cancer (GBC) is a rare disease with high mortality. However, no biomarkers for the carcinogenesis, progression, prognosis, and early diagnosis are clinically available. This study investigated the expressions of cystathionine-β-synthase (CBS) and C-C chemokine receptor 7 (CCR7) protein and their clinical and pathologic significances in gallbladder squamous cell/adenosquamous carcinomas (SC/ASC) and adenocarcinomas (AC). CBS and chemokine ligand 21 (CCL21) expression was measured using immunohistochemistry in 69 SC/ASCs and 146 ACs. A significantly high percentage of patients with an age above 45 years, lymph node metastasis, and invasion was observed in the SCs/ASCs compared with ACs (P<0.05). Both AC and SC/ASC patients with positive CBS and CCL21 expression exhibited a high tumor-lymph node-metastasis stage, lymph node metastasis, and invasion compared with patients with negative CBS and CCL21 expression (P<0.05 or P<0.01). SC/ASC patients with positive CBS expression was prone to have a larger tumor size than those with negative expression (P<0.05). Positive CBS and CCL21 expression correlated with poor differentiation and larger tumor size in AC patients. Positive CBS and CCL21 are closely associated with a decreased overall survival in SC/ASC and AC patients (P<0.05 or P<0.01) and were independent factors for a poor-prognosis. Both CBS and CCL21 showed a good overall diagnostic performance for SC/ASC (AUC=0.742 and AUC=0.764, respectively) and AC (AUC=0.734 and AUC=0.718, respectively). In conclusion, positive CBS and CCL21 expression are closely associated with the clinical severity and poor prognosis in GBC, and can be a marker for the diagnosis of AC and SC/ASC type of GBC.

This study was conducted to investigate the expressions of DDR2 and IFITM1 and their clinical and pathological significances in the rare type squamous cell/adenosquamous carcinomas (SC/ASC) and ordinary adenocarcinomas (AC) of gallbladder cancers. DDR2 and IFITM1 expression was examined in 69 SC/ASCs and 146 ACs using EnVision immunohistochemistry. Results showed that the percentage of positive DDR2 and IFITM1 expression was significantly higher in SC/ASC patients with high TNM stage, lymph node metastasis, invasion, and no resection surgery compared to patients with low TNM stages, no lymph node metastasis, no invasion, and resection surgery (P < 0.05 or P < 0.01). The positive rate of DDR2 was significantly higher in SC/ASC patients with large tumor sizes than patients with small tumor sizes (p < 0.05). The percentage of positive DDR2 and IFITM1 expressions was significantly higher in AC patients with high TNM stages that didn't receive resection surgery compared to patients with low TNM stages that did receive resection surgery (P < 0.05 or P < 0.01). The positive rate of IFITM1 was significantly higher in AC patients with lymph node metastasis and invasion than in patients without metastasis and invasion (p < 0.05). Positive DDR2 and IFITM1 expression was closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). AUC analysis showed that DDR2 and IFITM1 was sensitive and specific for the diagnosis of SC/ASC (AUC = 0.740 and AUC =0.733, respectively) and AC (AUC = 0.710 and AUC =0.741, respectively). In conclusion, positive DDR2 and IFITM1 expression is a marker for the clinical severity, poor prognosis, and diagnosis of gallbladder SC/ASC and AC.

Purpose: Gallbladder cancers (GBCs) are highly aggressive gastrointestinal cancers with high mortality. Biological markers for the diagnosis, prognosis, and targeted therapy of GBCs have not been established., Methods: The protein expression of Jagged1 and DLL4 in 80 adenocarcinomas (AC) and 46 squamous cell/adenosquamous carcinomas (SC/ASCs) was measured using immunohistochemistry., Results: Positive Jagged1 and DLL4 expression in both SC/ASC and AC was significantly associated with poor differentiation, large tumor size, invasion, metastasis, and low surgical curability. Univariate Kaplan-Meier analysis showed that positive Jagged1 and DLL4 expression was significantly associated with mean survival of SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Jagged1 and DLL4 expression, as well as poor differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and low surgical curability are independent poor prognostic factors in both SC/ASC and AC patients., Conclusions: Positive Jagged1 and DLL4 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in patients with SC/ASC and patients with AC.

Aim: To investigate the expression and clinical pathological significance of ROR2 and WNT5a in gallbladder squamous/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC)., Methods: EnVision immunohistochemistry was used to stain for ROR2 and WNT5a in 46 SC/ASC patients and 80 AC patients., Results: Poorly differentiated AC among AC patients aged > 45 years were significantly more frequent compared with SC/ASC patients, while tumors with a maximal diameter > 3 cm in the SC/ASC group were significantly more frequent compared with the AC group. Positive ROR2 and WNT5a expression was significantly lower in SC/ASC or AC with a maximal mass diameter ≤ 3 cm, a TNM stage of I + II, no lymph node metastasis, no surrounding invasion, and radical resection than in patients with a maximal mass diameter > 3 cm, TNM stage IV, lymph node metastasis, surrounding invasion, and no resection. Positive ROR2 expression in patients with highly differentiated SC/ASC was significantly lower than in patients with poorly differentiated SC/ASC. Positive ROR2 and WNT5a expression levels in highly differentiated AC were significantly lower than in poorly differentiated AC. Kaplan-Meier survival analysis showed that differentiation degree, maximal mass diameter, TNM stage, lymph node metastasis, surrounding invasion, surgical procedure and the ROR2 and WNT5a expression levels were closely related to average survival of SC/ASC or AC. The survival of SC/ASC or AC patients with positive expression of ROR2 and WNT5a was significantly shorter than that of patients with negative expression results. Cox multivariate analysis revealed that poor differentiation, a maximal diameter of the mass ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, unresected surgery and positive ROR2 or WNT5a expression in the SC/ASC or AC patients were negatively correlated with the postoperative survival rate and positively correlated with mortality, which are risk factors and independent prognostic predictors., Conclusion: SC/ASC or AC patients with positive ROR2 or WNT5a expression generally have a poor prognosis., Competing Interests: Conflict-of-interest statement: All authors declare that there are no commercial, personal or any other potential conflicting interests related to the submitted manuscript.

The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder remain to be fully elucidated, due to the fact that it is a rare gallbladder cancer subtype. In the current study, the expression of minichromosome maintenance complex component 2 (MCM2) and HIV‑1 tat interactive protein 2 (TIP30) was measured in 46 cases of SC/ASC and 80 adenocarcinomas (AC) using immunohistochemistry. Positive MCM2 and negative TIP30 expression were significantly associated with large tumor size, high TNM stage, invasion, lymph node metastasis and lack of surgical curability in SC/ASC and AC. Positive MCM2 and negative TIP30 expression were significantly associated with poor differentiation in AC, whereas only MCM2 was correlated with differentiation in SC/ASC. Univariate Kaplan‑Meier analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and surgical curability were significantly associated with post‑operative survival in patients with SC/ASC and AC. Multivariate Cox regression analysis demonstrated that positive MCM2 and negative TIP30 expression, the degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis and lack of surgical curability were also independent predictors of poor prognosis in patients with SC/ASC and AC. These data suggest that positive MCM2 and negative TIP30 expression are closely correlated with the clinical, pathological and biological parameters, in addition to poor prognosis in patients with gallbladder cancer.

Biomarkers for the diagnosis, prognosis, and targeting therapy of gallbladder cancers are not clinically available. This study demonstrated that the percentage of cases with positive SHP2 and UGP2 expression significantly correlated with the percentage of cases with positive vimentin, β-catenin, MMP2, MMP9, and Ki-67 expression, large tumor size, high TNM stage, lymph node metastasis, and survival in patients with adenocarcinomas and squamous cell/adenosquamous carcinomas. Positive SHP2 and UGP2 expression are independent poor-prognostic factors in both types of tumors. Our study suggested that positive SHP2 and UGP2 expression correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer.

Gallbladder cancers (GBCs) are highly malignant gastrointestinal cancers. The biological makers for the prognosis and targeting therapy of GBCs have not been established. The protein expression of Notch 1 and Notch 3 in 46 squamous cell/adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (AC) was measured using immunohistochemistry. Positive Notch 1 and Notch 3 expression in both SC/ASC and AC was significantly associated with large tumor size, invasion, metastasis, and low surgical curability (P < 0.05 or P < 0.01). Univariate Kaplan-Meier analysis showed that positive Notch 1 and Notch 3 expression was significantly associated with mean survival of SC/ASC and AC patients (P < 0.01 or P < 0.001). Multivariate Cox regression analysis showed that positive Notch 1 and Notch 3 expression, as well as low differentiation, large tumor size, high TNM stage, invasion, lymph node metastasis, and surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Positive Notch 1 and Notch 3 expression is closely correlated with severe clinicopathological characteristics and poor prognosis in both SC/ASC and AC patients.

The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented. This study investigates the clinical and pathological associations of ATP5B and β2M with benign and malignant lesions of the gallbladder. In this study, ATP5B and β2M expression in 46 SC/ASCs and 80 ACs were examined using immunohistochemistry. The rate of ATP5B positive expression was significantly lower, while the rate of β2M expression was significantly higher, in AC and SC/ASC than in gallbladder adenomas, gallbladder polyps, or gallbladder epithelium with stone (P < 0.01). More SC/ASCs had larger tumor mass and good differentiation compared to ACs. Positive β2M and negative ATP5B expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that positive β2M (P < 0.05 or P < 0.001) expression and negative ATP5B (P < 0.001) expression were significantly associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that negative ATP5B expression is an independent-prognostic factor for poor prognosis in both SC/ASC (P < 0.01) and AC (P < 0.001) patients. Positive β2M expression is an independent-prognostic factor for poor prognosis in AC (P < 0.05) patients. Our study suggested that positive β2M expression or loss of ATP5B expression in tumor tissues is closely related to the metastasis, invasion, and poor-prognosis of gallbladder cancer.

Gall bladder cancers (GBCs) are highly resistant to radiotherapy and chemotherapy. Unfortunately, the key molecular mechanisms responsible for therapeutic resistance have not been identified. In this study, the expression of DNA-PKcs and Ku70 in 46 squamous cell/adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (ACs) were examined by immunohistochemical analysis. Positive DNA-PKcs and Ku70 expression were significantly associated with less lymph node metastasis, invasion, and low TNM stage of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that loss of DNA-PKcs and Ku70 expression significantly correlated with decreased survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that loss of DNA-PKcs and Ku70 expression was an independent poor prognostic predictor in both SC/ASC and AC patients. Our study suggested that DNA-PKcs and Ku70 are tumor suppressors, and loss of DNA-PKcs and Ku70 expression is an important biological marker for metastasis, invasion, and prognosis of GBC. Currently, there is no implication of DNA-PKcs and Ku70 expression in chemoresistance or radioresistance in GBC.

Gallbladder cancer (GBC) is a rare, but highly aggressive cancer. The most common type of gallbladder cancer is adenocarcinoma (AC), while squamous cell/adenosquamous carcinoma (SC/ASC) is a rare type of gallbladder cancer. The clinicopathologic and biological characteristics of SC/ASC have not been well documented. In this study, the protein expression of N-cadherin and P-cadherin in 46 SC/ASCs and 80 ACs was measured using immunohistochemistry. We demonstrated that positive N-cadherin and P-cadherin expression were significantly associated with large tumor size, invasion, and lymph node metastasis of both SC/ASC and AC. In contrast, positive N-cadherin and P-cadherin expression were significantly associated with differentiation and TNM stage in only AC. Univariate Kaplan-Meier analysis showed that positive N-cadherin and P-cadherin expression, differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive N-cadherin and P-cadherin expression are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive N-cadherin and P-cadherin expression closely correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Aims: Squamous cell/adenosquamous carcinomas (SC/ASC) are rare subtypes of gallbladder cancers (GBCs). Clinical characteristics of SC/ASC have not been well documented, and no biological markers of GBC carcinogenesis, progression and prognosis are available., Methods and Results: We measured paxillin and CAIX expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) with immunohistochemistry and correlated these data with clinicopathological characteristics. Both paxillin expression and CAIX expression were associated significantly with larger tumours, a higher tumour-node-metastasis (TNM) stage, lymph node metastasis and invasiveness of SC/ASC and AC. Univariate Kaplan-Meier analysis confirmed that paxillin and CAIX expression were associated closely with decreased overall survival in SC/ASC (both P < 0.001) and AC (both P < 0.001). Multivariate Cox regression analysis confirmed that paxillin expression and CAIX expression both independently predicted poor prognosis in SC/ASC and AC patients. We also noted correlations with survival and tumour differentiation, tumour size, TNM stage, lymph node metastasis, tumour invasiveness and sample procurement methods., Conclusions: Paxillin expression and CAIX expression are both related to clinical/biological behaviour and poor prognosis of GBC., (© 2013 John Wiley & Sons Ltd.)

Background: The differences in clinical, pathological, and biological characteristics between adenocarcinoma (AC) and squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder cancer have not been well documented. This study is to compare the clinicopathological characteristics and FGFBP1 and WISP-2 expression between AC and SC/ASC patients., Methods: We examined FGFBP1 and WISP-2 expression in 46 SC/ASC and 80 AC samples using immunohistochemistry and analyzed their correlations with clinicopathological characteristics., Results: SC/ASCs occur more frequently in older patients and often correspond to larger tumor masses than ACs. Positive FGFBP1 and negative WISP-2 expression were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. In addition, positive FGFBP1 and negative WISP-2 expression were significantly associated with differentiation and TMN stage in ACs. Univariate Kaplan-Meier analysis showed that either elevated FGFBP1 (p < 0.001) or lowered WISP-2 (p < 0.001) expression was closely associated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive FGFBP1 expression (p = 0.001) or negative WISP-2 expression (p = 0.035 for SC/ASC and p = 0.009 for AC) is an independent predictor of poor prognosis in both SC/ASC and AC patients. We also revealed that differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical procedure were associated with survival of both SC/ASC and AC patients., Conclusion: Our study suggested that the overexpression of FGFBP1 or loss of WISP-2 expression is closely related to the metastasis, invasion and poor prognosis of gallbladder cancer.

Gallbladder cancers (GBCs) are highly aggressive and lethal diseases. However, the key molecular mechanisms responsible for the progression and prognosis of GBCs have not been identified. No biological markers for effectively identifying GBC subtypes have been reported. In this study the expression of keratin 19 (KRT19) and human achaete-scute homolog 1 (hASH1) proteins in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. Negative KRT19 or positive hASH1 expression were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASC patients. In contrast, positive KRT19 and hASH1 expression were significantly associated with large tumor size, lymph metastasis, invasion, and TNM stage in AC patients. Univariate Kaplan-Meier analysis showed that loss of KRT19 or elevated hASH1 expression significantly correlated with decreased survival in SC/ASC patients. In contrast, positive KRT19 and hASH1 expression correlated with a shorter survival time in AC patients. Multivariate Cox regression analysis showed that negative KRT19 expression or positive hASH1 expression was an independent poor-prognostic predictor in SC/ASC, but positive KRT19 and hASH1 expression were poor-prognostic factors in AC patients. Our study suggested that hASH1 can be used to determine the malignancy of SC/ASC and AC tumors and is associated with poor prognosis. In contrast, KRT19 is a protective factor in AC patients but a sign of malignancy in SC/ASC patients.

The clinicopathological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder have not been well documented, and no prognosis marker has been identified because of the rare occurrence of this gallbladder cancer subtype. In this study, we examined ACE2 and FZD1 expression in 46 SC/ASCs and 80 adenocarcinomas using immunohistochemistry and further analyzed their correlations with clinicopathological characteristics. We demonstrated that positive FZD1 and negative ACE2 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis and invasion of SC/ASC and AC. Univariate Kaplan-Meier analysis showed that positive FZD1 and negative ACE2 expression as well as differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability were closely associated with decreased overall survival in both SC/ASC (p < 0.001) and AC (p < 0.001) patients. The average survival time in SC/ASC and AC patients with FZD1(-)ACE2(+) expression was significantly longer than that in patients with FZD1(+)ACE2(-) or FZD1(+)ACE2(+) (p < 0.01). Multivariate Cox regression analysis showed that positive FZD1 and negative ACE2 expression are independent poor-prognostic factors for both SC/ASC and AC patients. In addition, FZD1 expression positively, but ACE2 expression negatively correlated with the expression of CA19-9 in SC/ASC and AC. Our study suggested that positive FZD1 and negative ACE2 expression are closely related to the expression of CA19-9; clinical, pathological, and biological behaviors; as well as poor-prognosis of gallbladder cancer.

Squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder are rare tumors and there are few clinical reports in the literature. Herein we report our clinical experience with 46 patients with SC/ASC and 80 with adenocarcinoma (AC). Expression of EphB1 and Ephrin-B in each tumor was determined using immunohistochemical methods for determination of correlations with prognosis. There was no difference in EphB1 and Ephrin-B expression between SC/ASC and AC tumors (P>0.05), but greater expression in those less than 3 cm in diameter, stage I or II (TNM stage), with no lymph node metastases, with no local invasion and treated with radical resection was apparent. Expression of EphB1 (P<0.05) and Ephrin-B (P<0.01) was higher in well differentiated than in poorly differentiated AC tumors. Kaplan-Meier survival analysis indicated that degree of differentiation, tumor diameter, lymph node metastases, local invasion, surgical approach and expression rate of EphB1 and Ephrin-B were closely related to the survival of SC/ASC (P<0.05) and AC patients (P<0.01). Patients with tumors that positive expressed EphB1 and Ephrin-B, whether it is SC/ASC (P SC/ASC =0.000) or AC (P AC =0.000 or P AC =0.002) had longer survival than those negative expression. Cox multivariate analysis indicated a negative correlation between expression of EphB1 or Ephrin-B and overall survival. Hence, EphB1 and Ephrin-B could be regarded as independent good prognostic factorsand important biological markers for SC/ASC and AC of gallbladder.

Background: Gallbladder cancer (GBC) is a relatively uncommon carcinoma among gastrointestinal cancers and usually has a rather poor prognosis. The most common subtype of GBC is adenocarcinoma (AC), which accounts for about 90% of GBC. Squamous carcinoma/adenosquamous carcinoma (SC/ASC) are comparatively rare histopathological subtypes of GBC. The clinicopathological features and biological behaviors of SC/ASC have not been well-characterized. No molecular biomarkers are currently available for predicting the progression, metastasis, and prognosis of the SC/ASC subtype of GBC., Methods: We examined the expression levels of CCT2 and PDIA3 by immunohistochemistry (IHC) staining in human GBC tissue samples collected from 46 patients with SC/ASC and evaluated the clinicopathological significance of both CCT2 and PDIA3 expression in the SC/ASC subtypes of GBC by Kaplan-Meier analysis and multivariate Cox regression analysis. For comparison, we included specimens from 80 AC patients in our study to investigate the specificity of CCT2 and PDIA3 expression in GBC subtypes., Results: We found that the positive expression of CCT2 and PDIA3 was significantly associated with clinicopathological features of both SC/ASC and AC specimens, including high TNM stage and lymph node metastasis. Univariate analysis revealed that the two-year survival rate was significantly lower for patients with positive expression of CCT2 and PDIA3 than for those with negative expression. Multivariate analysis also indicated that the positive expression of CCT2 and PDIA3 was negatively correlated with poor postoperative patient survival and positively correlated with high mortality., Conclusions: Our study suggests that positive expression of CCT2 or PDIA3 is associated with tumor progression and the clinical behavior of gallbladder carcinoma. Therefore, CCT2 and PDIA3 could be potentially important diagnostic and prognostic biomarkers for both SC/ASC and AC subtypes of GBC.

Gallbladder cancer (GBC) is one of the most aggressive tumors; we examined the expression level of DNA fragmentation factor 45 (DFF45) and thyroid transcription factor 1 (TTF-1) in benign and malignant lesions of the gallbladder by immunohistochemistry. The results were correlated with clinicopathological features and prognosis. DNA fragmentation factor 45 and TTF-1 expression was significantly higher in gallbladder adenocarcinomas than in the corresponding peritumoral tissues (χ²DFF45 = 6.92, χ²TTF-1 = 8.68, ps < 0.01), polyps (χ²DFF45 = 4.49, χ²TTF-1 = 5.35, ps < 0.05), and chronic cholecystitis (χ²DFF45 = 12.98, χ²TTF-1 = 17.74, ps < 0.01). Negative expression of DFF45 and TTF-1 was significantly associated with tumor differentiation, tumor mass, lymph node metastasis and invasion of adenocarcinomas (p < 0.05). Univariate Kaplan-Meier analysis showed that elevated expression levels of DFF45 and TTF-1 (p < 0.05) were closely associated with increased overall survival. In addition, the average survival time of patients with DFF45(+) TTF-1(+) tumors was significantly higher than those with DFF45(-) TTF-1(-) tumors (p < 0.05). Finally, multivariate Cox regression analysis showed that negative expression of DFF45 and TTF-1 was an independent prognostic predictor in gallbladder adenocarcinoma (p < 0.05). The expression of DFF45 and/or TTF-1 is closely related to the carcinogenesis, progression, clinical behavior and prognosis of gallbladder adenocarcinomas. DNA fragmentation factor 45 and TTF-1 could be progression-associated genes correlating with good prognosis in GBC.

Cofilin-1 (CFL1) and Arp3 expression in 46 squamous cell and adenosquamous carcinomas (SC/ASCs) and 80 adenocarcinomas (ACs) were measured by using immunohistochemistry. Positive CFL1 and Arp3 expression were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and decreased overall survival in both SC/ASC and AC patients (p < .001). Multivariate Cox regression analysis showed that positive CFL1 and Arp3 expression are independent poor-prognostic factors for both SC/ASC and AC patients. Our study suggested that positive CFL1 and Arp3 expression are closely related to tumor progression, metastasis, and poor prognosis of gallbladder cancer.

Although the incidence of gallbladder cancers is low, they are highly aggressive tumors. Squamous cell/adenosquamous carcinoma (SC/ASC) is a rare subtype of gallbladder cancer. The clinical characteristics of SC/ASC have not been well documented, and no prognosis marker has been identified. In this study, we examined integrin-linked kinase (ILK) and peroxiredoxin-1 (PRDX1) expression in 46 SC/ASCs and 80 adenocarcinomas (ACs) by using immunohistochemistry and analyzed their correlations with clinicopathological characteristics. We demonstrated that positive ILK and PRDX1 expressions were significantly associated with large tumor size, high TNM stage, lymph node metastasis, and invasion of SC/ASC and AC. Univariate Kaplan-Meier analysis showed that positive ILK and PRDX1 expressions were closely associated with decreased overall survival in both SC/ASC (p < 0.001 and p = 0.005, respectively) and AC (p < 0.001) patients. Multivariate Cox regression analysis showed that positive ILK and PRDX1 expressions were an independent poor prognostic predictor in both SC/ASC and AC patients. We also revealed a similar significance of differentiation, tumor size, TNM stage, lymph node metastasis, invasion, and surgical curability with survival in SC/ASC and AC patients. Our study suggested that positive ILK and PRDX1 expressions are closely related to the progression and poor prognosis of gallbladder cancer.

Background: Gallbladder cancers (GBCs) are highly aggressive cancers with high mortality. However, biological markers for the progression and prognosis of GBC are currently unavailable in the clinic., Objective: To identify biomarkers for predicting GBC metastasis and prognosis., Methods: We examined ALDH1A3 and GPX3 expressions in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) by using immunohistochemistry., Results: Positive ALDH1A3 and negative GPX3 expressions were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either positive ALDH1A3 (P < 0.001) or negative GPX3 (P < 0.001) expression significantly correlated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive ALDH1A3 expression or negative GPX3 expression was an independent poor-prognostic predictor in both SC/ASC and AC patients., Conclusions: Our study suggested that positive ALDH1A3 and negative GPX3 expressions are closely associated with clinical pathological behaviors and poor prognosis of gallbladder cancer.

PSCA and Oct-4 have been thought as markers of cancer stem cells. Although overexpression of PSCA and Oct-4 in cancer has been reported, little is known about the clinical and pathological significance with PSCA and Oct-4 expression in gallbladder adenocarcinoma. In this study, overexpression of PSCA and Oct-4 was detected in gallbladder adenocarcinoma (54.6% and 55.6%). Less expression of PSCA and Oct-4 was detected in the pericancerous tissues (19.6% and 21.7%), gallbladder polyps (13.3% and 13.3%), and gallbladder epithelium with chronic cholecystitis (14.3% and 14.3%). The overexpression of PSCA and Oct-4 was significantly associated with differentiation, tumor mass, lymph node metastasis, invasion of gallbladder adenocarcinoma, and decreased overall survival. Our study suggested that overexpression of PSCA and Oct-4 might be closely related to the carcinogenesis, progression, metastasis, or invasive potential and prognosis of gallbladder carcinoma.

The clinicopathological and biological characteristics of squamous cell/adenosquamous carcinoma (SC/ASC) of gallbladder have not been well documented because it is a rare subtype of gallbladder cancer. In this study, the protein expression of Nectin-2 and DDX3 in 46 SC/ASCs and 80 adenocarcinomas was measured using immunohistochemistry. We demonstrated that positive Nectin-2 and DDX3 expression was significantly associated with large tumor size, high TNM stage, and lymph node metastasis of SC/ASC and AC. Positive Nectin-2 and DDX3 expression was significantly associated with invasion and surgical curability of AC. Univariate Kaplan-Meier analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with post-operative survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive Nectin-2 and DDX3 expression, degree of differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and no surgical curability are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive Nectin-2 and DDx3 expression is closely correlated with clinical, pathological, and biological behaviors as well as poor-prognosis of gallbladder cancer.

Background: The objective of this study was to investigate CD9 and HMGA2 expression and its clinicopathological significance in benign and malignant lesion tissues of the gallbladder., Methods: The resected specimens of 108 cases of gallbladder adenocarcinoma, 46 cases of adjacent tissue, 15 cases of polyps and 35 cases of chronic cholecystitis were made into conventional paraffin-embedded sections, using the method of EnVision immunohistochemistry to stain HMGA2 and CD9., Results: HMGA2 expression of gallbladder adenocarcinoma was significantly higher than that of adenocarcinoma adjacent tissues (= 16.13, P <0.01), polyps (= 8.19, P <0.01) and chronic cholecystitis (= 21.41, P <0.01); but CD9 expression was the opposite (P <0.05 or P <0.01). The positive rate of HMGA2 expression from the cases that had well-differentiated adenocarcinoma, with the largest tumor diameter <2 cm, and without lymph node metastasis, and that did not invade the surrounding tissue was significantly lower than that of HMGA2 expression from the cases that had poorly differentiated adenocarcinoma, with the largest tumor diameter ≥2 cm, lymph node metastasis, and that invaded the surrounding tissues (P <0.05 or P <0.01). The positive rate of CD9 expression from the cases that had well-differentiated adenocarcinoma, with the largest tumor diameter <2 cm, and without lymph node metastasis, and that did not invade the surrounding tissue was significantly higher than that of CD9 expression from the cases that had poorly differentiated adenocarcinoma, with the largest tumor diameter ≥2 cm, lymph node metastasis, and which invaded the surrounding tissues (P <0.05 or P <0.01). The Kaplan-Meier survival analysis showed that after surgery, the survival period of HMGA2 expression-positive cases was significantly lower than that of HMGA2 expression-negative cases (P = 0.020), but the survival period of CD9 expression-positive cases was significantly higher than that of cases with CD9 expression-negative (P = 0.019). Cox multivariate regression analysis showed that the HMGA2 positive expression and/or CD9 negative expression was an important indicator reflecting the poor prognosis of gallbladder cancer., Conclusion: The expression of HMGA2 and/or CD9 might be closely related to the carcinogenesis, clinical biological behaviors and prognosis of gallbladder adenocarcinoma.