IL-8 is a novel prometastatic chemokine in intrahepatic cholangiocarcinoma that induces CXCR2-PI3K/AKT signaling upon CD97 activation.

Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive malignant tumor arising within the liver, with a 5-year survival rate of only 20-40% after surgery. The role of interleukin-8 (IL-8) in ICC progression remains elusive. A transcriptomic approach based on IL-8 stimulation first revealed significant upregulation of the prometastatic gene CD97 and key epithelial-mesenchymal transition (EMT) factors E-cadherin and vimentin. Immunohistochemistry of 125 ICC tissues confirmed the positive correlation between IL-8 and CD97. Multivariable Cox regression indicated that they are both independent predictors of ICC prognosis. Mechanistically, IL-8 treatment induced CD97 expression at 50 and 100 ng/ml in QBC-939 and QBE cells, respectively. Moreover, the induction of cell migration and invasion upon IL-8 treatment was attenuated by CD97 RNA interference, and the expression of EMT-associated genes was dramatically inhibited. To determine whether CXCR1 or CXCR2 are downstream effectors of IL-8, siCXCR2 was applied and shown to significantly attenuate the oncogenic effects of IL-8 by inhibiting the phosphorylation of PI3K/AKT. Finally, the induction of CD97 expression by the PI3K pathway was verified by treatment with the inhibitor LY294002. In vivo, the significant tumor growth and lung metastasis effects induced by intraperitoneal injection of IL-8 were greatly inhibited by silencing CD97 in nude mice. Collectively, the study presents a novel mechanism of the IL-8-CXCR2-PI3K/AKT axis in regulating CD97 expression, which leads to ICC metastasis mainly through EMT. The study may provide alternatives for targeting the tumor microenvironment in metastatic ICC.

Hepatic abscess caused by esophageal foreign body misdiagnosed as cystadenocarcinoma by magnetic resonance imaging: A case report.

BACKGROUND: Foreign bodies stuck in the throat and esophagus can be discharged through the digestive tract. Esophageal-lodged foreign bodies can cause secondary injury or detrimental response, with hepatic abscess being one such, albeit rare, outcome. Review and discussion of the few case reports on such instances will help to improve the overall understanding of such conditions and aid in differential diagnosis to improve patient outcome. CASE SUMMARY: A 51-year-old female patient with pre-existing diabetes visited our hospital following a 15-d experience of chills and fever. Both plain and enhanced magnetic resonance imaging and color Doppler ultrasound examination of the liver and gallbladder revealed a space-occupying lesion in the caudate lobe of the liver (7.8 cm × 6.0 cm × 5.0 cm). Initially, a malignant tumor was suspected, but differential diagnosis was unable to exclude the possibility of hepatic abscess. Conservative anti-infection therapy produced a less than ideal outcome. Additional examination by hepatobiliary imaging with computed tomography suggested a foreign body present in the upper abdomen and hepatic abscess, and subsequent endoscopy revealed a sinus tract in the anterior wall of the duodenal bulb. Therefore, surgery was performed to remove the object (fishbone) and drain the abscess. After a 2-wk uneventful recovery, the patient was discharged. The final diagnosis was foreign body-induced hepatic abscess of the caudate lobe. CONCLUSION: Differential diagnosis is important for hepatic masses, and systematic examination and physician awareness can aid in diagnosing and curing such rare conditions.

The Islanding effect - a special method of percutaneous peritumor ethanol injection for hepatocellular carcinoma: 15-year follow-up outcome.

ABSTRACT: Percutaneous ethanol injection is a well-known ablation therapy for hepatocellular carcinoma and is well-tolerated, inexpensive, and effective with few adverse events. In this study, another type of ethanol injection was introduced in the present study.Sixty two patients with hepatocellular carcinoma received 133 percutaneous peritumor ethanol injection treatments and the 15-year follow-up outcomes were analyzed through a collected database.The technical efficiency was 89.5% (119/133 treatments) after the first percutaneous peritumor ethanol injection procedure. However, after the second repeated percutaneous peritumor ethanol injection procedure, technical efficiency increased to 98.5% (131/133 treatments). The 1 year, 3 years, 5 years, 10 years, and 15 years rates of tumor recurrence were 12.9%, 50.0%, 59.7%, 74.2%, and 74.2%, respectively. Multivariate analysis demonstrated that diabetes, Child-Pugh class B, and tumor size greater than 2 cm were significantly related to tumor recurrence. The 1 year, 3 years, 5 years, 10 years, and 15 years rates of overall survival were 98.4%, 83.6%, 61.3%, 19.4%, and 0%, respectively. Multivariate analysis demonstrated that Child-Pugh class B, tumor size greater than 2 cm, and multiple tumors were significantly related to overall survival.Compared with other ablation methods (including peritumor ethanol injection), percutaneous peritumor ethanol injection can avoid tumor ruptures, reduce tumor proliferation and metastasis, and is suitable for the treatment of small tumors. In addition, when combined with other treatment methods, percutaneous peritumor ethanol injection can form a tumor metastatic isolation zone in advance and improve the comprehensive treatment effect.

Development and validation of novel nomograms for predicting the survival of patients after surgical resection of pancreatic ductal adenocarcinoma.

BACKGROUND/AIMS: Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality, even after surgical resection. The existing predictive models for survival have limitations. This study aimed to develop better nomograms for predicting overall survival (OS) and cancer-specific survival (CSS) in PDAC patients after surgery. METHODS: A total of 6323 PDAC patients were retrospectively recruited from the Surveillance, Epidemiology, and End Results (SEER) database and randomly allocated into training, validation, and test cohorts. Multivariate Cox regression analysis was conducted to identify significant independent factors for OS and CSS, which were used for construction of nomograms. The performance was evaluated, validated, and compared with that of the 8th edition AJCC staging system. RESULTS: Ten independent factors were significantly correlated with OS and CSS. The 1-, 3-, and 5-year OS rates were 40%, 20%, and 15%, and 1-, 3-, and 5-year CSS rates were 45%, 24%, and 19%, respectively. The nomograms were calibrated well, with c-indexes of 0.640 for OS and 0.643 for CSS, respectively. Notably, relative to the 8th edition AJCC staging system, the nomograms were able to stratify each AJCC stage into three prognostic subgroups for more robust risk stratification. Furthermore, the nomograms achieved significant clinical validity, exhibiting wide threshold probabilities and high net benefit. Performance assessment also showed high predictive accuracy and reliability. CONCLUSIONS: The predictive ability and reliability of the established nomograms have been validated, and therefore, these nomograms hold potential as novel approaches to predicting survival and assessing survival risks for PDAC patients after surgery.

A nomogram to predict lymph node metastasis before resection in intrahepatic cholangiocarcinoma.

BACKGROUND: In this study, we developed and validated a nomogram to predict lymph node metastasis before surgery in patients with intrahepatic cholangiocarcinoma (ICC). METHODS: Using the data from January 2006 to January 2015, we enrolled a total of 218 eligible patients with clinicopathologically confirmed ICC as a primary cohort to develop the nomogram. After various variables before surgery were analyzed by multivariable logistic regression, we combined the preoperative carbohydrate antigen 19-9, primary site of tumor, lymphonodus size on computed tomography imaging, tumor growth pattern, and (if applicable) histologic grade to make two different predictive nomograms. Then, the results were validated in 62 consecutive ICC patients from February 2015 to December 2016. We also compared the performance of the different nomograms via calibration, discrimination, and clinical use. RESULTS: The nomogram displayed fine discrimination (the concordance index, 0.761) and fine calibration in the primary cohort. When applied to the validation cohort, the nomogram also showed fine discrimination (concordance index, 0.794) and fine calibration. After adding the histologic grade to the nomogram, the integrated discrimination for predictive performance improved significantly. Finally, the clinical usefulness of predictive nomogram was proven via the decision curve analysis. CONCLUSIONS: The proposed nomograms can be selectively used to achieve more accurate lymph node metastasis predictions before surgery in patients with ICC, and this information can help with clinical management.

Macroscopic types of intrahepatic cholangiocarcinoma and the eighth edition of AJCC/UICC TNM staging system.

The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is undefined among the different macroscopic types. This study evaluated the viability of the American Joint Committee on Cancer (AJCC) 8th edition staging classification for different macroscopic types. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we enrolled a total of 2,679 eligible patients with an estimated 199 periductal infiltrating type of ICC (ICC-PI) patients and 2,480 mass-forming type of ICC (ICC-MF) patients. After conducting a multivariate Cox analysis, we found that the AJCC 8th edition staging system was suitable for ICC-MF patients but not for ICC-PI patients according to cancer-specific survival (CSS) and overall survival (OS). The main reason was the similar hazard ratio (HR) between the ICC-PI patients with stage I and stage II disease according to CSS (HR:0.969, P = 0.949) and OS (HR:0.832, P = 0.703). Moreover, we found that ICC-PI patients in AJCC stage I had a similar HR as ICC-MF patients in AJCC stage II according to CSS (HR: 1.208, P = 0.475) and OS (HR:1.206, P = 0.456). Therefore, we suggested that ICC-PI patients may be defined as T2, which is classified as stage II disease. This suggestion for the AJCC 8th edition staging system would be more suitable for different macroscopic types of ICC but requires further verification in prospective clinical trials.

Modified staging classification for intrahepatic cholangiocarcinoma based on the sixth and seventh editions of the AJCC/UICC TNM staging systems.

Intrahepatic cholangiocarcinoma (ICC) was differentiated from hepatocellular carcinoma, as defined in the American Joint Committee on Cancer (AJCC) 6th edition staging manual, using the revised staging system described in the AJCC 7th edition staging manual. This study was conducted to analyze the application of the AJCC 6th and 7th edition staging classifications and to evaluate a modified staging classification to potentially reduce the limitations associated with the different AJCC staging systems.We compared the prognostic value of cancer staging using data from the Surveillance, Epidemiology, and End Results database (N = 2124). The Kaplan-Meier method and Cox regression models were used to analyze survival. The Harrell concordance index (C-index) was used to analyze the discriminative abilities of cancer staging.Patients with stages I and II disease were found to have similar prognoses according to the 6th edition staging system. Using the 7th edition staging system, a low proportion of patients had stage III disease (5.0%), and the hazard ratio (HR) for stage III disease was comparable to that of stage IV disease (stage III and IV, 2.653 and 2.694). We modified the AJCC staging classification by adopting the 7th edition T, N, and M definitions and the 6th edition staging definitions. Consequently, the proportion of patients with stage III disease increased (22.8%). The HR for stage IV disease was higher than that for stage III disease (stage III and IV, 2.425 and 2.956). Meanwhile, the C-index of the modified AJCC staging system was 0.721 (95% CI: 0.696-0.745), which was significantly higher than the AJCC 7th edition staging system (0.694, P < .001), and the AJCC 6th edition staging system (0.712, P = .033). Moreover, in the stratified data, the differences between the stages identified using the modified AJCC staging classification were significant, especially among patients over 60 years in age, white patients and patients who underwent surgery.These findings suggest that the modified AJCC staging classification may be applicable to the staging of ICC and can be adopted in clinical practice.

Expression and prognostic value of soluble CD97 and its ligand CD55 in intrahepatic cholangiocarcinoma.

The incidence rate of intrahepatic cholangiocarcinoma is rising, and treatment options are limited. Therefore, new biological markers of intrahepatic cholangiocarcinoma are needed. Immunohistochemistry and enzyme-linked immunosorbent assay were applied to analyze the expressions of CD97, CD55, and soluble CD97 in 71 patients with intrahepatic cholangiocarcinoma and 10 patients with hepatolithiasis. CD97 and CD55 were not expressed in hepatolithiatic tissues, but positive expression was observed in 76.1% (54/71) and 70.4% (50/71) of intrahepatic cholangiocarcinoma patients. The univariate analyses indicated that the positive expressions of CD97 and CD55 were related to short intrahepatic cholangiocarcinoma survival of patients (both p = 0.001). Furthermore, CD97 and CD55 expressions and biliary soluble CD97 levels were significantly associated with histological grade (p = 0.004, 0.002, and 0.012, respectively), lymph node metastases (p = 0.020, 0.038, and 0.001, respectively), and venous invasion (p = 0.003, 0.002, and 0.001, respectively). The multivariate analyses indicated that lymph node metastases (hazard ratio: 2.407, p = 0.003), positive CD55 expression (hazard ratio: 4.096, p = 0.003), and biliary soluble CD97 levels (hazard ratio: 2.434, p = 0.002) were independent risk factors for the intrahepatic cholangiocarcinoma survival. The receiver operating characteristic (ROC) curve analysis indicated that when the cutoff values of biliary soluble CD97 were 1.15 U/mL, the diagnostic value for predicting lymph node metastasis had a sensitivity of 87.5% and a specificity of 51.3%. For intrahepatic cholangiocarcinoma patient death within 60 months at a cutoff value of 0.940 U/mL, the diagnostic value sensitivity was 89.3% and the specificity was 93.3%. Biliary soluble CD97 may be a new biological marker for early diagnosis, prediction of lymph node metastasis and poor prognosis, and discovery of a therapeutic target.

Risk Factors for Cholangiocarcinoma After Initial Hepatectomy for Intrahepatic Stones.

BACKGROUND: Aggressive hepatectomy is effective in treating intrahepatic stones and may minimize the deleterious consequences of subsequent cholangiocarcinoma (S-CCA). The risk factors of S-CCA after different methods of hepatectomy may vary with the resection scope of stone-affected segments. METHODS: We reviewed the records of 981 patients of primary intrahepatic stones with elective hepatectomy from January 2000 to December 2010. The clinical characteristics of patients in the S-CCA group (n = 55) and the control group (n = 926) were compared. The uniformity between extent of liver resection (ELR) with stone-affected segments (SAS) was segmented into 2 varieties: ELR = SAS with ELR < SAS according to the different hepatic resection scopes. Cox regression model with forward selection was used to identify the risk factors of S-CCA. RESULTS: In the univariate analysis, significant differences were observed between the S-CCA and control groups concerning stone location (unilateral 43.6 and 65.2 %, bilateral 56.4 and 34.8 %), residual stones (32.7 and 11.6 %), hepaticojejunostomy (43.6 and 30.9 %), and uniformity between ELR with SAS (ELR = SAS 20.0 and 42.6 %, ELR < SAS 80.0 and 57.4 %). Residual stones [hazard ratio (HR) 2.101, P = 0.016], hepaticojejunostomy (HR 1.837, P = 0.026) and uniformity between ELR and SAS (HR 2.442, P = 0.013) were independent prognostic factors for S-CCA by a Cox regression analysis with forward selection. In the subsection of ELR = SAS group, the 5- and 10-year postoperative tumor occurrence rates of unilateral and bilateral stones group were 0.9 versus 1.9 % and 3.0 versus 4.1 %, respectively (P = 0.663, log-rank). In the other subsection of ELR < SAS group, the 5- and 10-year postoperative tumor occurrence rates of unilateral and bilateral stones group were 3.4 versus 3.9 % and 6.8 versus 13.2 %, respectively (P = 0.047, log-rank), and the 5- and 10-year postoperative tumor occurrence rates of residual stones and non-residual stones group were 5.8 versus 3.0 % and 16.0 versus 7.9 %, respectively (P = 0.015, log-rank). CONCLUSIONS: Patients who underwent aggressive hepatectomy and had ELR = SAS had better outcomes than those with ELR < SAS. In the patients with ELR = SAS, the S-CCA rates of unilateral and bilateral stones were low and comparable. However, patients with ELR < SAS and bilateral intrahepatic or residual stones should be monitored more carefully for high-risk factors of S-CCA.

Serum vascular endothelial growth factors C and D as forecast tools for patients with gallbladder carcinoma.

Gallbladder carcinoma (GBC) is the most common cancer of the biliary tract. Lymph node metastasis (LNM) is the major diffusion route of GBC and is a prognosis factor. The aim of study was to assess the potential of the serum VEGF-C and VEGF-D (sVEGF-C/D) levels to predict the presence of LNM and the survival of GBC patients. The preoperative sVEGF-C/D levels of 31 patients with GBC, 10 patients with cholesterol polyps, and 10 healthy volunteers were measured by enzyme-linked immunoadsorbent assay (ELISA). The sVEGF-C/D levels of patients with GBC were significantly higher than those of people with healthy gallbladders (p < 0.001 and p = 0.001, respectively) and cholesterol polyp (p = 0.032 and p = 0.004, respectively). In GBC, the sVEGF-C levels were associated with LNM (p = 0.011), distant metastasis (p = 0.018), and stage (p = 0.045), but the sVEGF-D levels had a significant association with the tumor depth (p = 0.001), LNM (p = 0.001), distant metastasis (p = 0.047), and stage (p = 0.002). The sVEGF-C/D diagnostic values for the presence of GBC were sensitivity of 71.0 and 74.2 % and specificity of 80.0 and 85.0 %, respectively. With respect to the diagnosis of LNM, the diagnostic values of sVEGF-C/D were as follows: sensitivity 81.2 and 87.5 % and specificity 73.3 and 80.0 %, respectively. The mean survival time with high sVEGF-C was significantly shorter than that with low sVEGF-C (p < 0.001), which was also true for low sVEGF-D (p = 0.032). The preoperative sVEGF-C/D levels might be reliable biomarkers for the presence of disease and LNM in patients with GBC. The sVEGF-C/D levels may be prognosis factors that can predict a poor outcome for GBC patients.

Risk factors of liver metastasis in patients after radical resection of pancreatic cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To analyze the risk factors of liver metastasis in patients after radical resection of pancreatic cancer.</p><p><b>METHODS</b>One hundred and twenty-four patients with non-metastatic, resectable pancreatic cancer treated in our department between 2006 and 2012 were included in this study. All of these patients underwent resection of the primary tumor combined with extensive lymph node dissection. The development of postoperative liver metastases was carefully followed up, and the clinicopathological factors and molecular characteristics were evaluated by univariate analysis and multivariate logistic regression using SPSS 16.0 software.</p><p><b>RESULTS</b>Forty-eight cases of liver metastases were found among the 124 cases of pancreatic cancer after radical surgery (38.7%). The rate of liver metastasis of pancreatic cancer after radical surgery in the age groups < 40, 40-60, and > 60 were 68.8%, 33.3% and 35.1%, respectively. The rate of liver metastasis in the body mass index (BMI) group < 20 kg/m2, 20-25 kg/m2, and > 25 kg/m2 were 21.6%, 44.1% and 52.6%, and the rate of liver metastasis in the time between the onset and diagnosis groups ≥ 3 months and < 3 months were 59.4% and 31.5%, respectively. The rate of liver metastasis in patients with preoperative fatty liver was 14.3% and it was 43.7% in patients without preoperative fatty liver. The rate of liver metastasis in patients of histological high, medium and low grade was 10.0%, 35.4% and 49.0%, respectively. The rate of liver metastasis in patients with venous tumor thrombus was 68.8% and it was 34.3% in patients without venous tumor embolus. The rate of liver metastasis in patients with postoperative chemotherapy was 31.2% and it was 51.1% in patients without postoperative chemotherapy. All those differences had statistical significance (P < 0.05). Univariate analysis revealed that age, body mass index (BMI), time between the onset and diagnosis, preoperative fatty liver, histological grading, tumor invasion depth, venous tumor embolus, and postoperative chemotherapy were significantly related to postoperative liver metastasis. Multivariate analysis revealed five statistically independent risk factors for postoperative liver metastasis: BMI, time between onset and diagnosis, preoperative fatty liver, histological grading, and venous tumor embolus.</p><p><b>CONCLUSIONS</b>Our data suggest that patient's BMI, time between onset and diagnosis, histological grade, and venous tumor embolus are significantly correlated with postoperative liver metastases in patients with pancreatic cancer. Pancreatic cancer patients with preoperative fatty liver have less postoperative liver metastasis.</p>