Long-term prognosis of patients with gallbladder carcinoma after curative-intent resection based on changes in the ratio of carbohydrate antigen 19-9 to total bilirubin (CA19-9/TB): a multicenter retrospective cohort study.

BACKGROUND: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients. METHODS: Prospectively colleced data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analysed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×103 U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS. RESULTS: The normal group (n=179 patients) and the normalization group (n=73 patients) had better OS and RFS than the non-normalization group (n=65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P<0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P=0.255; RFS, P=0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P=0.025; RFS, P=0.003). CONCLUSIONS: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients.

Textbook outcomes in liver surgery for gallbladder cancer patients treated with curative-intent resection: a multicenter observational study.

BACKGROUND: Cholecystectomy, hepatectomy, and lymphadenectomy are recommended as the curative treatment for resectable gallbladder cancer (GBC). Textbook outcomes in liver surgery (TOLS) is a novel composite measure that has been defined by expert consensus to represent the optimal postoperative course after hepatectomy. This study aimed to determine the incidence of TOLS and the independent predictors associated with TOLS after curative-intent resection in GBC patients. METHODS: All consecutive GBC patients who underwent curative-intent resection between 2014 and 2020 were enrolled from a multicenter database from 11 hospitals as the training and the internal testing cohorts, and Southwest Hospital as the external testing cohort. TOLS was defined as no intraoperative grade greater than or equal to 2 incidents, no grade B/C postoperative bile leaks, no postoperative grade B/C liver failure, no 90-day postoperative major morbidity, no 90-day readmission, no 90-day mortality after hospital discharge, and R0 resection. Independent predictors of TOLS were identified using logistic regression and were used to construct the nomogram. The predictive performance was assessed using the area under the curve and calibration curves. RESULTS: TOLS was achieved in 168 patients (54.4%) and 74 patients (57.8%) from the training and internal testing cohorts, and the external testing cohort, respectively. On multivariate analyses, age less than or equal to 70 years, absence of preoperative jaundice (total bilirubin≤3 mg/dl), T1 stage, N0 stage, wedge hepatectomy, and no neoadjuvant therapy were independently associated with TOLS. The nomogram that incorporated these predictors demonstrated excellent calibration and good performance in both the training and external testing cohorts (area under the curve: 0.741 and 0.726). CONCLUSIONS: TOLS was only achieved in approximately half of GBC patients treated with curative-intent resection, and the constructed nomogram predicted TOLS accurately.

Targeting CXCL5 in Pancreatic Cancer Cells Inhibits Cancer Xenograft Growth by Reducing Proliferation and Inhibiting EMT Progression.

BACKGROUND: Pancreatic cancer (PC) is the most lethal malignant tumor, with average survival period of about 10 months. C-X-C ligand 5 (CXCL5), an important chemokine for immune cell accumulation in tumor tissues, has been reported to be involved in a variety of human cancers. However, the exact role of CXCL5 in PC progression has not been well defined. METHODS: The expression of CXCL5 in PC was analyzed based on online databases and clinical specimens immunohistochemical staining, and Western blotting of CXCL5 in PC cell lines and patient samples. The correlation between CXCL5 expression and prognosis in PC was explored. The role of CXCL5 in PC was investigated through in vitro and in vivo experiments. RESULTS: The expression of CXCL5 was significantly increased in PC tissues compared with that in pancreas tissues, and CXCL5 high expression predicts poor prognosis in PC patients. Further analyses demonstrated that overexpression of CXCL5 in PC cells was positively related to higher proliferation rate, higher migration ability, and higher EMT markers including SNAI2 and TWIST1 of tumor cells in vitro. Consistently, the knockdown of CXCL5 in PC cells harmed the proliferation rate, migration ability, and expression of EMT indexes of tumor cells in vitro. Importantly, knockdown of CXCL5 inhibited the growth of xenograft tumors in vivo. CONCLUSION: CXCL5 high expression predicts poor prognosis in PC patients. CXCL5 promotes PC cell growth and EMT process. Inhibition of CXCL5 may be a potential therapeutic approach for PC.

Association between high levels of Notch3 expression and high invasion and poor overall survival rates in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a commonly fatal tumour. It is characterized by early metastasis and high mortality. Many patients die as a result of PDAC tumour progression. However, the underlying mechanism of invasion and metastasis in PDAC is still not fully understood. Previous studies showed that the Notch signalling pathway may play an important role in the progression of tumour invasion and metastasis. However, it is not yet known whether the Notch signalling pathway participates in the progression of invasion in PDAC. In the present study, immunohistochemistry showed that a high expression of Notch3 was correlated with tumour grade, metastasis, venous invasion and American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage. Kaplan-Meier curves suggested that a high expression of Notch3 was a significant risk factor for shortened survival time. We also showed that inhibition of Notch3 had an anti­invasion role in PDAC cells. In vitro, the inhibition of Notch3 reduced the migration and invasion capabilities of PDAC cells by regulating the expressions of E-cadherin, CD44v6, MMP-2, MMP-9, VEGF and uPA via regulating the COX-2 and ERK1/2 pathways. These results indicated that downregulation of the Notch signalling pathway may be a novel and useful approach for preventing and treating PDAC invasion.

[Loss of expression and mechanism of early growth response gene-3 in human oral squamous carcinoma].

OBJECTIVE: To evaluate the expression of early growth response gene-3 (EGR3) in human oral squamous carcinoma tissue, non-adjacent tissue and oral carcinoma cell lines and detect the effects of EGR3 expression on the biological behaviors of oral squamous carcinoma cell lines. METHODS: From October 2008 to December 2009, the expression of EGR3 was detected in 20 human oral squamous carcinoma tissue, non-tumor adjacent tissue and 2 oral carcinoma cell lines. The total-length plasmid of EGR3 was constructed and transfected into oral squamous carcinoma line Tca-8113 to observe the proliferation and apoptosis. RESULTS: There was a high-level expression of EGR3 mRNA in normal oral squamous epithelial and non-tumor adjacent tissues (2.108 ± 0.996 and 1.721 ± 1.196). And a low-level expression or a loss of EGR3 mRNA in human oral squamous carcinoma tissue and oral carcinoma cell lines (0.007 ± 0.005 and 0.007 ± 0.001) (both P < 0.05). Tca-8113 transfected by EGR3 plasmid had a high-level expression of EGR3 mRNA capable of inhibiting the proliferation of Tca-8113 and promoting its apoptosis dramatically. The stimulating index in overexpression of EGR3 was lower than control group (0.35 ± 0.11 vs 0.82 ± 0.21, P < 0.05). After overexpression of EGR3 in Tca-8113, the frequency of middle-Late stage of apoptosis (Annexin-V/PI double positive) was higher than the frequency of vector group (23.12% ± 6.65% vs 5.96% ± 0.98%, P < 0.05). CONCLUSION: A low-level expression or a loss of EGR3 in human oral squamous carcinoma and an over-expression of EGR3 in human oral squamous carcinoma may inhibit the proliferation and promote apoptosis of oral squamous carcinoma.

[Clinical value of iodine [131I] metuximab infusion combined with TACE for treatment of patients with post-intervention relapse of mid or advanced stage hepatocellular carcinoma].

OBJECTIVE: To evaluate the clinical value of iodine[131I] metuximab infusion combined with transcatheter arterial chemoembolization (TACE) for treating cases of post-intervention relapse of mid or advanced stage hepatocellular carcinoma (HCC). METHODS: Sixty patients who were diagnosed between March 2009 and June 2010 with relapse of mid or advanced stage HCC following previous intervention with various standard clinical methods were recruited for study. The patients were randomly and equally divided into a control treatment group (CG; receiving TACE therapy alone) and an experimental treatment group (TG; receiving TACE combined with iodine [131I] metuximab injection). For all patients, licartin was first perfused into the tumor feeding artery and then the TACE procedure was performed 20 min later. Liver function markers and routine blood parameters, including alpha-fetoprotein (AFP) and clotting time, were examined at one week and one month after the treatment. Enhanced computed tomography or magnetic resonance imaging of the liver was performed at one month after treatment and thereafter on a bi-monthly follow-up schedule. The World Health Organization's tumor evaluation standard was used to assess the therapeutic effects in each group. Results of laboratory tests (pre- and post-treatment), reported complications, and side-effects were evaluated for their contributions to time of tumor progression (TTP) and survival time. RESULTS: Patients in the TG and CG groups had similar blood cell counts at pre-operative and 1-week postoperative time points. The TG group showed a significantly reduced level of AFP following treatment, but it was not significantly different from the level in the CG group. The TG group did however show significantly different levels of liver functional parameters (all P less than 0.05) and significantly higher TTP (4.84+/-4.11 vs. CG: 2.54+/-2.08 months; t = -2.13, P less than 0.05) and average survival time (7.05 vs. 5.15 months; x2 = 4.24, P = 0.039). The rates of partial response (PR), slight remission (MR), unchanged status (SD) and progressive disease (PD) were 16.7%, 37.5%, 25.0% and 20.8% in the TG group, and 8.7%, 17.4%, 21.7% and 52.2% in the CG group. The therapeutic effect rate (CR + PR + MR) and reaction rate (CR + PR + MR + SD) was significantly different between the two groups (P = 0.048). No serious adverse effects were reported. CONCLUSION: TACE combined with iodine [131I] metuximab injection is a safe and effective procedure for prolonging the survival and TTP of patients with HCC relapse following prior therapeutic intervention.

[Clinical efficacy of malignant obstructive jaundice treated by domestic biliary metallic stent insertion].

OBJECTIVE: To evaluate the clinical efficacy of implanted biliary metallic stents in the management of malignant obstructive jaundice (MOJ). METHODS: Percutaneous transhepatic cholangiography and stent insertion were performed in 241 consecutive patients to treat malignant biliary obstruction between December 1998 and February 2009. The study end point was patient death. All patients were followed-up until death or until February 2010. The therapeutic efficacy was determined by statistical analysis of life span and pre- and post-operative laboratory indices. RESULTS: All 241 patients were successfully stented. The level of bilirubin descended obviously within four weeks of implantation (P less than 0.05), and the early mortality rate was 4.56% (11/241). Two-hundred-and-two patients were followed-up (range: 8-193 weeks post-transplantation) and showed a median survival of 43.55 weeks. The survival rates at 13, 26, 39 and 52 weeks post-transplantation were 87%, 66%, 56%, and 41%, respectively. The stent patency rates at 13, 26, 39 and 52 weeks post-transplantation were 70%, 46%, 36% and 24%, respectively; the mean stent patency was 27.57 weeks. Cox regression analysis identified the strong predictors of improved survival as an initial bilirubin level of less than 221 mumol/L (P = 0.01) and a stent-induced bilirubin reduction of more than 50% (P = 0.002). CONCLUSION: Transhepatic metallic biliary stenting is a safe and effective therapeutic intervention for malignant biliary obstruction. Significant periods of survival and palliation of jaundice can be achieved with this method. Hyperbilirubinemia and a stent-induced bilirubin reduction of less than 50% are independent predictive factors for the survival of MOJ patients.

Expression and prognostic significance of cancer-testis antigens (CTA) in intrahepatic cholagiocarcinoma.

BACKGROUND: Cancer-testis antigens (CTAs) are suitable targets for cancer-specific immunotherapy. The aim of the study is to investigate the expression of CTAs in intrahepatic cholagiocarcinoma (IHCC) and evaluate their potential therapeutic values. METHODS: Eighty-nine IHCC patients were retrospectively assessed for their expression of CTAs and HLA Class I by immunohistochemistry using the following antibodies: MA454 recognizing MAGE-A1, 57B recognizing multiple MAGE-A (MAGE-A3/A4), E978 recognizing NY-ESO-1, and EMR8-5 recognizing HLA class I. The clinicopathological and prognostic significance of individual CTA markers and their combination were further evaluated. RESULTS: The expression rates of MAGE-A1, MAGE-A3/4 and NY-ESO-1 were 29.2%, 27.0% and 22.5%, respectively. The concomitant expression of CTAs and HLA class I antigen was observed in 33.7% of the IHCC tumors. We found that positive MAGE-3/4 expression correlated with larger tumor size (≥ 5 cm), tumor recurrence and poor prognosis. Moreover, we identified 52 cases (58.4%) of IHCC patients with at least one CTA marker expression, and this subgroup displayed a higher frequency of larger tumor size and a shorter survival than the other cases. Furthermore, expression of at least one CTA marker was also an independent prognostic factor in patients with IHCC. CONCLUSION: Our data suggest that specific immunotherapy targeted CTAs might be a novel treatment option for IHCC patients.

[Hepatectomy with portal vein resection and reconstruction in the treatment of hilar cholangiocarcinoma].

OBJECTIVE: To summarize the clinical experience and the role of hepatectomy with portal vein resection and reconstruction hilar cholangiocarcinoma. METHODS: From 1998 to 2003, the clinical records of 118 cases with hilar cholangiocarcinoma were reviewed. RESULTS: Of the 118 patients, 66 were performed palliative treatment; and 52 patients underwent radical resection, of which 47 patients, including 11 cases combined with portal vein resection and reconstruction, underwent hepatectomy. The rate of postoperation complication was 22.9% and 27.3% in hepatectomy with or without portal vein resection and reconstruction respectively. The 1, 3-year survival rate were 85.7%, 31.4% and 81.8%, 27.8% in hepatectomy with or without portal vein resection and reconstruction respectively (P > 0.05). Only 5 patients were alive more than 3 years (7.58%), and no patient with palliative treatment lived over 5 years. CONCLUSIONS: Portal vain invasion is not the contraindication of resection for hilar cholangiocarcinoma. Hepatectomy with portal vein resection and reconstruction may raise the radical resection rate of hilar cholangiocarcinoma and improve the results of prognosis.