Treatment Of Gallbladder Carcinoma Research Articles

EMP3 as a key downstream target of miR-663a regulation interferes with MAPK/ERK signaling pathway to inhibit gallbladder cancer progression

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, and its molecular pathogenesis remains unclear. Here we explore the functional roles of epithelial membrane protein 3 (EMP3) in GBC progression, which is aberrantly expressed in various types of cancers. The results showed that the expression level of EMP3 was reduced in human GBC tissues compared with non-malignant tissues. Further, the low expression of EMP3 was associated with the poor prognosis of GBC patients by Kaplan-Meier analysis. The ectopic expression of EMP3 inhibited GBC cell proliferation, migration and invasion in vitro and in vivo. Conversely, the depletion of EMP3 promoted GBC cell growth and metastasis. In addition, we found that EMP3 was a target gene of miR-663a, and the downregulation of EMP3 in GBC was attributed to the overexpression of miR-663a. MiR-663a was also shown to be a tumor-promoting factor mediating GBC development. In this study, we demonstrate that downregulation of EMP3 activates MAPK/ERK signaling, which regulates GBC progression. These data reveal the mechanism by which EMP3 inhibits the progression of GBC, suggesting that the miR-663a/EMP3/MAPK/ERK axis may be a new therapeutic target for GBC treatment.

Current status and progress in laparoscopic surgery for gallbladder carcinoma.

Gallbladder carcinoma (GBC) is the most common biliary tract malignancy associated with a concealed onset, high invasiveness and poor prognosis. Radical surgery remains the only curative treatment for GBC, and the optimal extent of surgery depends on the tumor stage. Radical resection can be achieved by simple cholecystectomy for Tis and T1a GBC. However, whether simple cholecystectomy or extended cholecystectomy, including regional lymph node dissection and hepatectomy, is the standard surgical extent for T1b GBC remains controversial. Extended cholecystectomy should be performed for T2 and some T3 GBC without distant metastasis. Secondary radical surgery is essential for incidental gall-bladder cancer diagnosed after cholecystectomy. For locally advanced GBC, hepatopancreatoduodenectomy may achieve R0 resection and improve long-term survival outcomes, but the extremely high risk of the surgery limits its implementation. Laparoscopic surgery has been widely used in the treatment of gastrointestinal malignancies. GBC was once regarded as a contraindication of laparoscopic surgery. However, with improvements in surgical instruments and skills, studies have shown that laparoscopic surgery will not result in a poorer prognosis for selected patients with GBC compared with open surgery. Moreover, laparoscopic surgery is associated with enhanced recovery after surgery since it is minimally invasive.

Expression of ER, PR, and HER-2 Neu and correlation with tumor markers in gall bladder carcinoma.

Females having a large proportion of gallbladder carcinoma (GBC) and a higher incidence of gallstones pointed toward the role of sex hormones in GBC development. In this study, we evaluated the expression of Estrogen receptor (ER), Progesterone receptor (PR), and Her2/neu and their correlation with tumor markers and clinicopathological parameters in the GBC. A total of 50 patients of GBC and 42 patients in control group undergoing surgery for other conditions were taken. The patient's biopsy sample's paraffin block was tested for ER, PR, and Her2/neu expression by immunohistochemistry. ER and PR had no significant expression in GBC and control group, but Her2/neu had 16% expression in GBC, significantly associated with the degree of differentiation with 62.5% (n-5) being well-differentiated; 75% of Her2/neu positive were in stages III and IV. Her2/neu did not correlate with tumor markers despite expression. Her2/neu amplification is a small step in validating that option so it could be included in the treatment and prognostication of GBC.

AFAP1-AS1/Hsa-miR-15a-5p/Bcl-2 Axis is a Potential Regulator of Cancer Cell Proliferation and Apoptosis in Gallbladder Carcinoma

Objective Gallbladder carcinoma (GBC) is a common malignancy of the biliary tract that, with late diagnosis, is often fatal. A better understanding of the underlying molecular mechanisms may facilitate targeted therapy for GBC. Therefore, this study aimed to investigate whether long non-coding RNA AFAP1-AS1 regulates GBC cell proliferation and apoptosis through hsa-miR-15a-5p. Methods SGC-996 and NOZ cell lines were transfected with an hsa-mR-15a-5p inhibitor or si-AFAP1-AS1, and GBC cell proliferation and apoptosis were measured. The expression levels of AFAP1-AS1, hsa-miR-15a-5p, apoptosis-related proteins, and bcl-2 were assessed. The dual-luciferase reporter assay was used to determine the binding between AFAP1-AS1 and hsa-miR-15a-5p or between hsa-miR-15a-5p and bcl-1. Results In SGC-996 and NOZ cells, AFAP1-AS1 was significantly expressed and hsa-miR-15a-5p was modestly expressed. Transfection of the hsa-miR-15a-5p inhibitor elevated proliferation of SGC-996 and NOZ cells and decreased apoptosis, whereas transfection of si-AFAP1-AS1 reduced the proliferation rate and increased apoptosis. In addition, AFAP1-AS1 bound hsa-miR-15a-5p and hsa-miR-15a-5p targeted bcl-2. Increased bcl-2 expression was observed in the GBC cells. AFAP1-AS1 may regulate GBC cell proliferation and apoptosis via has-miR-15a-5p to mediate bcl-2 expression. Conclusion The AFAP1-AS1/hsa-miR-15a-5p/bcl-2 axis regulates GBC cell proliferation and apoptosis, providing potential guidance for the clinical treatment of GBC.

Recognition of potential therapeutic role of 2-hydroxy-3-methylanthraquinones in the treatment of gallbladder carcinoma: A proteomics analysis.

Gallbladder carcinoma (GBC), with early metastasis and high recurrence rates, is an enormous threat to health. As an anthraquinones monomer of traditional Chinese medicine Hedyotis diffusa, 2-hydroxy-3-methylanthraquinone (HMA) has been reported to inhibit the growth of several cancers. But in our preliminary study, HMA could only weakly induce GBC cell apoptosis. To explore other possible mechanism underlying the inhibition effect of HMA on GBC, this proteomics analysis was performed. A proteomics analysis was performed on one GBC cell line bought from the China Life Science Cell Bank. Several computational techniques were merged to develop analysis for those differently expressed proteins. A comparative protein-protein interaction network analysis was carried out among the differently expressed proteins to identify the proteins potentially inhibiting GBC. Thus, a GO and KEGG analysis was performed to identify the signaling pathways underlying a potential therapeutic role for HMA. A total of 285 proteins were affected by HMA, including 187 upregulated and 98 downregulated. The subcellular localization of differently expressed proteins were identified, including 142 in nuclear, 67 in cytoplasm, 67 in extracellular matrix, 46 in plasma membrane, 13 in mitochondrion, 3 in lysosome, and 1 in cytoskeleton. HMA could regulate EGFR, FN1, PLG, PLAUR, LAMA3, HRG, THBS1, PLAT, KNG1, ENAM, SERPINE1, ECM1, interleukin-8, and trypsin in GBC. Most of the regulated proteins involve in cell migration. Pathways including PI3K-Akt, Wnt, HIF-1, focal adhesion, microRNAs were regulated by HMA. HMA was shown to be an inhibition agent for GBC development, and this analysis would contribute to the development of new anti-GBC drugs.

Long Non-Coding RNA Myosin Light Chain Kinase Antisense 1 Plays an Oncogenic Role in Gallbladder Carcinoma by Promoting Chemoresistance and Proliferation.

BackgroundLong non-coding RNAs (lncRNAs) have been reported to play critical roles in human tumours, including gallbladder carcinoma (GBC). However, their biological functions and molecular mechanisms in tumorigenesis and progression remain largely unknown.MethodsQuantitative polymerase chain reaction (qPCR) was used to verify the expression of lncRNA myosin light chain kinase antisense RNA 1 (MYLK-AS1) in 120 pairs of GBC tissues and paired adjacent non-tumour tissues, as well as in six different GBC cell lines (NOZ, EH-GB1, OCUG-1, GBC-SD, SGC-996 and QBC-939). Cell counting kit 8 was applied to explore cell proliferation and drug sensitivity assays. The target miRNAs (miR) of MYLK-AS1 and downstream target genes were predicted using Starbase 3.0 software and confirmed by double luciferase reporting test. The expression of proteins was assessed using Western blot assay.ResultsHere, we demonstrated that MYLK-AS1 was significantly upregulated and correlated with a poor prognosis and poor clinical characteristics in GBC. Furthermore, the forced expression of MYLK-AS1 significantly promoted GBC cell proliferation and resistance to gemcitabine in vitro. Mechanistically, MYLK-AS1 functioned as an efficient miR-217 sponge, thereby releasing the inhibition of enhancer of zeste 2 polycomb repressive complex 2 (EZH2) subunit expression. MYLK-AS1 promoted GBC cell proliferation and resistance to gemcitabine by upregulating EZH2 expression, and EZH2 was confirmed as a direct target of miR-217.DiscussionOur results confirmed that the chemoresistant driver MYLK-AS1 might be a promising candidate as a therapeutic target for the treatment of advanced GBC.

Attach importance to the standardized diagnosis and treatment of gallbladder carcinoma

Gallbladder carcinoma,characterized by concealed onset,rapid development,and poor prognosis,needs to be valued by clinicians.The key to improving its prognosis remains early diagnosis and standardized therapy.Improving the sensitivity and accuracy of hematological and imaging diagnosis and early detection of specific molecular diagnostic targets for gallbladder cancer are helpful for early diagnosis and treatment.It is of great importance to emphasize on intraoperative reassessment and select the correct surgical procedures.It is the primary condition for increasing the R0 radical resection rate and improving the prognosis that prudentially carrying out laparoscopic radical resection and referring to standardized resection of cancer foci and regional lymph node removal.In the future,guided by concepts of oncology,comprehensive treatment of multiple modes,containing surgery,chemotherapy,targeted,immune and biological therapy,is the development trend of gallbladder cancer treatment,which requires high-quality clinical research and interdisciplinary cooperation.

The immunological characteristics of gallbladder carcinoma and advances in immunotherapy practices.

Gallbladder carcinoma (GBC) is one of the most common malignant tumors in the biliary system, ranking sixth among gastrointestinal malignancies. In addition, the incidence of GBC has recently increased in China. GBC metastasizes early and invades adjacent organs such as the liver, making patients with GBC ineligible for radical surgery and giving them a poor prognosis. What is more, GBC is more inclined to develop chemo-resistance, which requires new strategies for clinical intervention. Cancer immunotherapy has made great advances over the past few years, with improved clinical efficacy against multiple malignancies, including GBC. This review summarizes the immunological characteristics of GBC as well as current advances in immunotherapies for GBC in order to provide new insights into future treatment and prevention of GBC.

Gallbladder Carcinoma in Portugal: A Single Center Experience and Prognostic Factors for Survival

Purpose: To identify clinicopathological prognostic factors for survival in patients with gallbladder carcinoma (GBC) submitted to surgery in our institution–a tertiary centre. Methods: 41 patients underwent surgical treatment for GBC between 2008-2019. 26(63.4%) were female, 28(68.3%) had associated cholelithiasis and the majority of tumours, 35(85.4%), were adenocarcinomas. 41.5% were diagnosed incidentally, 65.9% had symptoms and 26.8% presented with acute cholecystitis. 46.3% were stage III (AJCC) or higher. 39% were submitted to cholecystectomy alone and 61% were also submitted to hepatic resection. 46.3% had vascular invasion, 26.8% hepatic parenchyma invasion and 9.8% bile duct invasion. Survival analysis was conducted on SPSS. Our institution ethics committee approved this work. Results: Median overall survival (OS) was 20.5 months (IQR 8.8-53.8). 3-year and 5-year survival rates were of 43.2% and 39.6%, respectively. On immunohistochemistry analysis, 6 patients (14.6%) were HER2+, but the HER2 status didn't show influence on OS (median OS 18 vs 20 months, p=0.649); all had microsatellite stability. There was no association between HER2 expression and staging (p=0.35). On univariate regression, the following factors were associated with worse OS: acute cholecystitis(HR 2.59 (95%CI 1.11-6.06), p=0.028), jaundice(HR 3.18 (95%CI 1.37-7.334), p=0.007), other carcinomas (HR 3.32 (95%CI 1.19-9.23), p=0.022), stage ≥ III(HR 10.35 (95%CI 2.34-45.75), p=0.002), N+(HR 6.55 (95%CI 2.38-18.03), p<0.001), vascular invasion(HR 8.96 (95%CI 2.78-28.89), p<0.001), hepatic invasion(HR 6.86 (95%CI 2.51-18.75), p<0.001), bile duct invasion(HR 3.50 (95%CI 1.11-11.02), p=0.033), ≥R1 resection(HR 11.79 (95%CI 3.8-36.6), p<0.001), CA 19.9 ≥500 U/mL(HR 2.5 (95%CI 1.05-5.98), p=0.039), CEA ≥5 ng/mL(HR 2.99 (95%CI 1.10-8.14), p=0.032); hepatic resection was associated with better OS(HR 0.24 (95%CI 0.11-0.67), p<0.001). On multivariate regression, stage ≥ III(HR 8.58, (95%CI 1.786-41.171), p=0.007), hepatic resection(HR 0.288, (95%CI 0.091-0.910), p=0.034) and vascular invasion(HR 4.06, (95%CI 1.035-15.918), p=0.045) were independently associated with OS. Conclusions: This study on GBC is, as far as the authors know, the first in Portugal. Surgery is still the gold standard for curative treatment and some patients with favourable prognosis may be identified. The overexpression of HER2 could select patients for targeted treatment and prompt tissue sampling in unresectable patients.

Immunohistochemical Expression of HER2/neu, Ki-67 and MUC1 in Benign and Malignant Gall Bladder Lesions and its Association with Clinicopathological Parameters

Introduction: Gall Bladder Carcinoma (GBC) is a diagnostic and a therapeutic challenge. Although it is increasing, chronic cholecystitis remains the most worldwide gall bladder lesions, harbouring many epithelial changes that may end in carcinoma. Aim: To investigate the expression of HER2/neu (Human Epidermal Growth Factor Receptor 2), Ki-67 and MUC1 (Mucin 1) in malignant and non-malignant gall bladder lesions, and to evaluate its relation with clinicopathologic parameters of GBC. Materials and Methods: This retrospective study included 40 cases of GBC, eight cases of gall bladder dysplasia, 10 cases of gall bladder metaplastic changes and 25 cases of chronic cholecystitis as a control group. The blocks were collected from the Department of Pathology of Benha University Hospital, from January 2012 to December 2019. Immunohistochemical staining results of HER2/neu, Ki-67 and MUC1 were analysed and correlated by Statistical Package for the Social Sciences (SPSS) version 16 and Chi-square test or Fisher’s-exact tests. Results: Positive HER2/neu expression (+2, +3) was detected in 47.5% (19/40) of malignant cases and 12.5% (1/8) of dyspastic group, at the same time it was completely absent in the metaplastic and cholecystitis cases (p&lt;0.01). Similarly, Ki-67 Labeling Index (LI) (≥20%) expression was found in 55% (22/40) of malignant group, while it was completely absent in the other three studied groups. All cases of malignant group 100% (40/40), 50% (4/8) of dysplastic one, one case of metaplastic (1/10) showed cytoplasmic expression of MUC1, at the same time it was completely absent in control group (0/25) (p&lt;0.01). High MUC1 expression was found in 75% of both malignant (30/40) and dysplastic (6/8) studied cases and only one case (10%) of metaplastic group (p&lt;0.01). There was a significant correlation between MUC1 expression and studied parameters of GBC. Conclusion: HER2/neu, and Ki-67 are overexpressed in GBC cases compared with control and dysplastic group. The study also highlights that MUC1 would be a better marker of malignant transformation of gall bladder epithelium and its depolarised expression would be reliable for detection of invasive carcinoma, so a new therapeutic agent can target these cell surface adhesion molecule (MUC1). HER2/neu can be considered as a candidate for targeted therapy in GBC treatment strategy.

Immunoproteomics approach revealed elevated autoantibody levels against ANXA1 in early stage gallbladder carcinoma

BackgroundEarly diagnosis is important for the timely treatment of gallbladder carcinoma (GBC) patients and may lead to increased survival outcomes. Here, we have applied serological proteome analysis (SERPA), an immunoproteomics approach, for the detection of ‘tumor-associated antigens (TAAs) that elicit humoral response’ in early stage GBC patients.MethodsTotal protein from pooled tumor tissue of GBC patients (n = 7) was resolved by two-dimensional gel electrophoresis (2-DE) followed by immunoblotting using pooled blood plasma from healthy volunteers (n = 11) or gallstone disease (GSD) cases (n = 11) or early stage GBC (Stage I and II) (n = 5) or GBC stage IIIA (n = 9). 2-D gel and immunoblot images were acquired and analyzed using PDQuest software to identify immunoreactive spots in GBC cases in comparison to controls. Proteins from immunoreactive spots were identified by liquid chromatography- tandem mass spectrometric analysis (LC-MS/MS). Autoantibody levels for two of the functionally relevant proteins were investigated in individual plasma samples (52 cases and 89 controls) by dot blot assay using recombinant proteins.ResultsImage analysis using PDQuest software identified 25 protein spots with significantly high or specific immunoreactivity in GBC cases. Mass spectrometric analysis of 8 corresponding protein spots showing intense immunoreactivity (based on densitometric analysis) in early stage GBC or GBC stage IIIA cases led to the identification of 27 proteins. Some of the identified proteins include ANXA1, HSPD1, CA1, CA2, ALDOA and CTSD. Among the two proteins, namely ANXA1 and HSPD1 verified using a cohort of samples, significantly elevated autoantibody levels against ANXA1 were observed in early stage GBC cases in comparison to healthy volunteers or GSD cases (unpaired t-test, p < 0.05). Receiver operating characteristic (ROC) curve analysis for ANXA1 showed an Area under the Curve (AUC) of 0.69, with 41.7% sensitivity against a specificity of 89.9% for early stage GBC. IHC analysis for ANXA1 protein showed ‘high’ expression levels in 72% of GBC cases whereas all the controls showed ‘low’ expression levels.ConclusionsThe study suggests that the ANXA1 autoantibody levels against ANXA1 may be potentially employed for early stage detection of GBC patients. Other proteins could also be explored and verified in a large cohort of clinical samples.

Oroxylin A Exerts Its Antitumor Effects in Human Gallbladder Cancer via Inhibition of the PTEN/PI3K/AKT Signaling Pathway.

Gallbladder carcinoma (GBC) is one of the most common carcinomas of the biliary tract and is associated with aggressive malignancy and poor prognosis. Current therapeutic strategies, including surgery, radiotherapy, and chemotherapy, are not sufficient for the treatment of GBC, and new therapeutic strategies are urgently needed. The antitumor effects of oroxylin A (OrA), a natural flavonoid extracted from the dried roots of medicinal plants such as Scutellariae species (Radix Scutellariae), have been widely reported in various cancers. In this study, we first evaluated the antitumor activity and the underlying mechanism of action of OrA on GBC cells in vitro. Our results revealed that OrA significantly attenuated the proliferation, migration, and invasion of GBC cells, simultaneously promoting their apoptosis. Suppression of the phosphate on and tension homology deleted chromosome ten (PTEN)/phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling pathway was found to be the underlying mechanism involved in the antitumor activity of OrA. In addition, experiments using a tumor xenograft mouse model confirmed the antitumor effects of OrA in vivo. Taken together, our findings indicate that OrA could be a potential antitumor agent for the prospective treatment of GBC.

Circular RNA circ-MTO1 serves as a novel potential diagnostic and prognostic biomarker for gallbladder cancer.

Primary gallbladder carcinoma (GBC) is one of the most common biliary malignancies in the gastrointestinal tract. In this work, we examined the roles of circular-mitochondrial translation optimization 1 (circ-MTO1) in GBC tissues and patient plasma. Circ-MTO1 expression in GBC tissues and patient plasma was evaluated by quantitative Real Time-PCR (qRT-PCR). The relationships between circ-MTO1 expression and the pathological characteristics of GBC were analyzed. Kaplan-Meier survival curve was applied to calculate overall survival (OS) and progression-free survival (PFS) in GBC patients with different circ-MTO1 expression. The univariate COX regression curve analysis method was employed to analyze the potential relationships between high circ-MTO1 expression and OS and PFS. At last, we assessed the diagnostic value of the circ-MTO1 level in GBC patient plasma. Circ-MTO1 expression was significantly upregulated in tumor tissues and plasma in GBC patients. In addition, circ-MTO1 expression was associated with clinical-pathological characteristics in GBC. High circ-MTO1 expression served as an independent prognostic factor for poor OS and PFS in GBC patients. Moreover, upregulated plasma circ-MTO1 level was significantly associated with tumor development. Circ-MTO1 is a potential early diagnostic and prognostic biomarker for patients with gallbladder cancer. Thus, our present work might provide a new understanding of the diagnosis and treatment of GBC.

The progress on survival prediction model of gallbladder carcinoma

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, radical resection is the only effective treatment for GBC at present. However, the postoperative effect is still poor. Therefore, identifying the key prognostic factors and establishing an individual and accurate survival prediction model for GBC are critical to prognosis assessment, treatment options and clinical decision support in patients with GBC. The prediction value of current commonly used TNM staging system is limited. Cox regression model is the most commonly used classical survival analysis method, but it is difficult to establish the association between prognostic variables. Nomogram and machine learning techniques including Bayesian network have been used to establish survival prediction model of GBC in recent years, which representing a certain degree of advancement, however, the model precision and clinical application still need to be further verified. The establishment of more accurate survival prediction models for GBC based on machine learning algorithm from Chinese multicenter large sample database to guide the clinical decision-making is the main research direction in the future.

Current status and future perspectives of minimally invasive surgery in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is the most common biliary tract malignancy, which is characterized by easy local invasion, lymph nodes metastasis, local vascular invasion. Hence, minimally invasive surgery (MIS) can be performed in a limited number of patients. In our study, we reviewed the current studies on laparoscopic surgery (LS) and robotic surgery (RS) for GBC and analysed the limitations and difficulties of MIS for GBC. Multiple electronic databases were used for a systematic literature retrieval. All studies involving MIS of GBC were included (up to August 2019). A total of 24 studies were included, of which 18 studies involved LS for GBC and six studies concerned RS of GBC. For LS, 16 studies contained relevant information of T stage, and 323 patients (98.8%) had T3 or lower stage; the average rate of R0 resection, conversion, postoperative complications and mortality was 95.3% (range 80.5-100%), 1.9% (range 0-16.7%), 13.4% (range 0-33.3%) and 1.0% (range 0-10%), respectively. For RS, four studies contained relevant information of T stage, and all patients were T3 or lower stage; the average rate of R0 resection, conversion and postoperative complications was 96.8% (range 81.8-100%), 5.5% (range 0-14.8%) and11.9% (range 0-36.4%), respectively. In addition, no patient had perioperative mortality. MIS for GBC is limited to highly selected patients and is considered to be technically feasible in experienced surgeons. However, improvements in technical and instrumental are needed to reduce the associated postoperative complications and implantation metastasis, and to promote MIS in the treatment of GBC.

Computer-aided assessment of the chemokine receptors CXCR3, CXCR4 and CXCR7 expression in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is a vicious and invasive disease. The major challenge in the clinical treatment of GBC is the lack of a suitable prognosis method. Chemokine receptors such as CXCR3, CXCR4 and CXCR7 play vital roles in the process of tumour progression and metastasis. Their expression levels and distribution are proven to be indicative of the progression of GBC, but are hard to be decoded by conventional pathological methods, and therefore, not commonly used in the prognosis of GBC. In this study, we developed a computer‐aided image analysis method, which we used to quantitatively measure the expression levels of CXCR3, CXCR4 and CXCR7 in the nuclei and cytoplasm of glandular and interstitial cells from a cohort of 55 GBC patients. We found that CXCR3, CXCR4 and CXCR7 expressions are associated with the clinicopathological variables of GBC. Cytoplasmic CXCR3, nuclear CXCR7 and cytoplasmic CXCR7 were significant predictive factors of histology invasion, whereas cytoplasmic CXCR4 and nuclear CXCR4 were significantly correlated with T and N stage and were associated with the overall survival and disease‐free survival. These results suggest that the quantification and localisation of CXCR3, CXCR4 and CXCR7 expressions in different cell types should be considered using computer‐aided assessment to improve the accuracy of prognosis in GBC.

Comparison of overall survival in gallbladder carcinoma at academic versus community cancer centers: An analysis of the National Cancer Data Base.

Gallbladder carcinoma (GBC) has a poor prognosis. Studies demonstrated that teaching facilities may provide a lower risk of mortality in patients undergoing pancreatic and colon resection vs nonteaching facilities. We hypothesized that survival rates are higher in academic cancer centers (ACCs) vs community cancer centers (CCCs). Patients with all stages of GBC were identified from the National Cancer Database (2007-2012). Propensity score matching adjusted for selection bias. Descriptive statistics were calculated for all variables. Overall survival (OS) was compared by facility type (ACC vs CCC) and case volume (low vs high) via multivariable Cox proportional hazards regression. A total of 7967 patients met the inclusion criteria. Following propensity matching, 2801 patients were analyzed from each facility type. Median OS following surgery was higher for ACC (20.99 months, 95% confidence interval [CI], 19.61-22.64, P = .002) than CCC (17.68 months, 95% CI, 16.46-19.25). Following Cox modeling, GBC treatment at ACCs was a protective factor for OS (adjusted hazard ratio 0.876, 95% CI, 0.801-0.958, P = .004). GBC treatment at ACCs is an independent predictor of OS. High volume ACCs are associated with improved OS compared with low volume ACCs. The site of care and case volume in ACCs may contribute to improved survival outcomes.

TFAP2A is a novel regulator that modulates ferroptosis in gallbladder carcinoma cells via the Nrf2 signalling axis.

Ferroptosis is a recently identified form of controlled cell death generally associated with the accumulation of lipid-associated reactive oxygen species (ROS). However, the molecular mechanisms underlying ferroptosis have not been established. Microarray expression data for three human gallbladder carcinoma (GBC) and matched non-tumour specimens were downloaded from the Gene Expression Omnibus (GEO) repository. Candidate genes were filtered using bioinformatic analysis. After cell transfection, candidate gene impacts on cell proliferation, migration, invasion and ferroptosis (ferrous iron (Fe2+) and malondialdehyde (MDA) levels) were assessed. We screened 626 differentially expressed genes (DEGs) including 465 that were downregulated and 161 that were upregulated in the three tissue pairs. These DEGs were used to construct a protein-protein interaction (PPI) network. Functional enrichment analysis revealed the top three modules in the network and four hub genes. Transcription factor AP-2 alpha (TFAP2A) was screened and showed overexpression in The Cancer Genome Atlas (TCGA) digestive system tumour data and a relationship with clinical survival. In vitro, GBC exhibited upregulated expression of TFAP2A, whose inhibition reduced GBC cell proliferation, migration, and invasion. Fe2+ and MDA levels were elevated. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed TFAP2A enrichment in oxidative stress. Subsequent experiments demonstrated that TFAP2A silencing attenuated the expression of key genes associated with oxidative stress such as heme oxygenase 1 (HO-1), nuclear factor erythroid 2 like 2 (Nrf2), ferritin heavy chain 1 (FTH1) and NAD(P)H quinone dehydrogenase 1 (NQO1). Bioinformatic and experimental analyses reveal that TFAP2A plays a vital role in ferroptosis and hence is a potential therapeutic target for GBC treatment.

Guideline for the diagnosis and treatment of gallbladder carcinoma (2019 edition)

In order to improve the overall therapeutic effect of gallbladder cancer in China, Branch of Biliary Surgery, Chinese Surgical Society and Chinese Committee of Biliary Surgeons have formulated the guideline for the diagnosis and treatment of gallbladder carcinoma (2019 edition) . The guideline provided an overview of the evidence on epidemiological risk factors, treatment and follow-up strategies for patients with gallbladder cancer.It also updated the new TNM stage and proposed the clinical classification of gallbladder cancer for the first time. The guideline highlighted the importance of accurate prediction of TNM stage and type of gallbladder cancer based on modern high-quality imaging technology and endoscopic techniques.The idea of comprehensive treatment should be established as the fundamental principle for patients with advanced gallbladder cancer, and a multidisciplinary approach is recommended to make optimal clinical decisions. Standard radical surgical treatment should be delivered by a team of experienced hepato-pancreato-biliary surgeons and pathologists.The combination regimens of chemotherapy, radiotherapy, targeted therapy and immunotherapy for gallbladder cancer have shown promise in improving prognosis. Further research is still needed to confer greater survival benefits to patients with gallbladder cancer.

Disparities in Treatment for Gallbladder Carcinoma: Does Treatment Site Matter?

Background and PurposeCurrent treatment guidelines for gallbladder cancer range from simple cholecystectomy to regional hepatic resection. Treatment patterns for radical resection and adjuvant chemotherapy vary. We aim to determine if there is any disparity in treatment or difference in survival between academic versus community treatment centers. MethodsThe National Cancer Database (NCDB) was queried from 2004 to 2014 for gallbladder carcinoma. Cases were stratified into treatment sites as “Community Cancer Center” (CCC) or “Academic Cancer Center” (ACC). Propensity score matching was performed for patient demographics, TNM stage, resection type, and administration of adjuvant chemotherapy. The primary outcome included 30-day mortality, 90-day mortality, and overall survival. ResultsThere are similar frequencies of radical versus simple resection and administration of adjuvant chemotherapy between ACC and CCC. When propensity-matched for resection type, cases treated at ACC have lower 30-day mortality (4.1% vs. 6.9%) and 90-day mortality (13.2% vs. 18.5%) and increased 5-year overall survival (26.2% vs. 22.4%) (p < 0.01). After propensity matching for adjuvant chemotherapy, cases at ACC have lower 30-day mortality (4.12% vs. 7.71%) and 90-day mortality (13.22% vs. 19.19%) and increased overall survival (13.6% vs. 11.0%) (p < 0.01). Discussion and ConclusionsWhile treatment patterns for gallbladder cancer at ACC and CCC were similar, there was a decrease in 30-day and 90-day mortality and improved overall survival associated with patients treated at ACC. Treatment site may have an impact in the surgical outcomes of gallbladder cancer patients. This disparity warrants further research.