Relationship between PD-L1 expression, CD8+ T-cell infiltration and prognosis in intrahepatic cholangiocarcinoma patients.

BACKGROUND: Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. METHODS: In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. RESULTS: The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p < 0.05). The expression of PD-L1 in the tumor was correlated with poor overall survival(OS) (p = 0.004), and the number of tumor and interstitial CD8+ T-cells was correlated with poor OS and disease-free survival (DFS) (All p < 0.001). CONCLUSIONS: The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.

The efficacy of combination of induction chemotherapy and irreversible electroporation ablation for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: Irreversible electroporation (IRE) is a non-thermal focal therapy that utilizes high voltage electric pulses to permanently rupture the cellular membrane and induce cell death. In this multi-center study, we evaluated the safety and efficacy of IRE in patients with locally advanced pancreatic cancer (LAPC). METHODS: From 2012 to 2015, we performed laparotomic and laparoscopic IRE in a total of 70 patients with stage III LAPC. Either gemcitabine-based or TS-1 (Tegafur, Gimeracil, and Oteracil) chemotherapy was applied for at least 3 months before the IRE. RESULTS: No IRE-related deaths occurred. A median follow-up of 28.1 months showed that six patients (8.6%) experienced local recurrence and 24 (34%) experienced distant progression. The overall median survival from the time of treatment was 22.6 months, and the progression-free survival (PFS) was 15.4 months. The overall survival in the patients who used gemcitabine-based reagents was 19.1 months and that of those who used TS-1 was 28.7 months. The PFS for these two groups were 13.2 months and 26.4 months; the difference is significant. CONCLUSIONS: Our study suggests that IRE is safe and effective for the control of LAPC. We surmise that the addition of IRE to a chemotherapy regimen may provide a survival advantage.

Contribution of contrast-enhanced sonography in the detection of intrahepatic cholangiocarcinoma.

OBJECTIVES: The purpose of this study was to evaluate the contribution of contrast-enhanced sonography in the diagnosis of intrahepatic cholangiocarcinoma up to 3 cm and analyze its dynamic enhancement patterns. METHODS: Forty-five patients (29 male and 16 female; mean age ± SD, 61.3 ± 10.7 years; range, 38-79 years) with a preliminary diagnosis of intrahepatic cholangiocarcinoma by contrast-enhanced sonography were retrospectively analyzed. For each nodule, the enhancement pattern, level, and dynamic change during the arterial, portal, and late phases after the injection of a sulfur hexafluoride microbubble contrast agent were evaluated. RESULTS: Among the 35 patients with a histopathologic diagnosis of intrahepatic cholangiocarcinoma, 18 nodules showed hyperenhancement during the arterial phase, and 17 showed hypoenhancement. Heterogeneous, peripheral, and partial enhancement were found in 24, 8, and 2 nodules, respectively. However, only 1 nodule showed homogeneous enhancement. During the portal phase, 34 nodules showed hypoenhancement, and 1 showed isoenhancement. Hypoenhancement during the late phase was observed in all cases. Ten patients had a misdiagnosis of intrahepatic cholangiocarcinoma. CONCLUSIONS: Intrahepatic cholangiocarcinoma up to 3 cm may display a variety of arterial enhancement patterns on contrast-enhanced sonography. However, some other nodules may manifest findings similar to those of intrahepatic cholangiocarcinoma.

Comparison of prognosis and postoperative morbidities between standard pancreaticoduodenectomy and the TRIANGLE technique for resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Radical surgery combined with systemic chemotherapy offers the possibility of long-term survival or even cure for patients with pancreatic ductal adenocarcinoma (PDAC), although tumor recurrence, especially locally, still inhibits the treatment efficacy. The TRIANGLE technique was introduced as an extended dissection procedure to improve the R0 resection rate of borderline resectable or locally advanced PDAC. However, there was a lack of studies concerning postoperative complications and long-term outcomes of this procedure on patients with resectable PDAC. AIM: To compare the prognosis and postoperative morbidities between standard pancreaticoduodenectomy (PD) and the TRIANGLE technique for resectable PDAC. METHODS: Patients with resectable PDAC eligible for PD from our hospital between June 2018 and December 2021 were enrolled in this retrospective cohort study. All the patients were divided into PDstandard and PDTRIANGLE groups according to the surgical procedure. Baseline characteristics, surgical data, and postoperative morbidities were recorded. All of the patients were followed up, and the date and location of tumor recurrence, and death were recorded. The Kaplan-Meier method and log-rank test were used for the survival analysis. RESULTS: There were 93 patients included in the study and 37 underwent the TRIANGLE technique. Duration of operation was longer in the PDTRIANGLE group compared with the PDstandard group [440 (410-480) min vs 320 (265-427) min] (P = 0.001). Intraoperative blood loss [700 (500-1200) mL vs 500 (300-800) mL] (P = 0.009) and blood transfusion [975 (0-1250) mL vs 400 (0-800) mL] (P = 0.009) were higher in the PDTRIANGLE group. There was a higher incidence of surgical site infection (43.2% vs 12.5%) (P = 0.001) and postoperative diarrhea (54.1% vs 12.5%) (P = 0.001) in the PDTRIANGLE group. The rates of R0 resection and local recurrence, overall survival, and disease-free survival did not differ significantly between the two groups. CONCLUSION: The TRIANGLE technique is safe, with acceptable postoperative morbidities compared with standardized PD, but it does not improve prognosis for patients with resectable PDAC.

Lymphadenectomy with venation is preferred compared to skeletonization for patients with rectal and sigmoid colon cancer: a retrospective cohort study.

Background: For patients with rectal and sigmoid colon cancer, dissecting No. 253 lymph nodes and preserving the left colic artery are the essentials of radical surgery. In clinical work, some surgeons prefer to dissect lymph nodes with skeletonization, believing that lymph nodes can be dissected completely by this method, while other surgeons prefer to dissect lymph nodes with venation. They believe that their method can not only dissect lymph nodes completely but also ensure the safety of patients. This study aimed to investigate whether lymphadenectomy with skeletonization is superior to lymphadenectomy with venation for patients with rectal and sigmoid colon cancer. Methods: We performed a retrospective cohort study between August, 2017 and October, 2019 at the Department of General Surgery, the Affiliated Hospital of Nanjing University Medical School. The inclusion criteria were as follows: diagnosed as rectum or sigmoid colon adenocarcinoma by electronic colonoscopy and histopathology; 18-80 years of age; underwent radical resection. The exclusion criteria were as follows: received neoadjuvant therapy before surgery; combined with distant metastasis. According to the method of lymph node dissection, patients were divided into the skeletonization group and venation group. We then compared the curative effect and safety between the 2 groups. Results: A total of 211 patients were recruited in this retrospective study and assigned as follows: 62 cases to the skeletonization group and 149 patients to the venation group. There were no statistical differences in the total number of lymph nodes (P=0.082), number of positive lymph nodes (P=0.097), total number of No. 253 lymph nodes (P=0.096), number of positive No. 253 lymph nodes (P=0.813), and nodal staging (P=0.254) between the 2 groups. However, the amount of bleeding in the skeletonization group was significantly higher than that in the venation group (P≤0.001), and the operation time in the skeletonization group was also significantly longer than that in the venation group (P≤0.001). Conclusions: Lymphadenectomy with venation is preferred in the radical resection of patients with rectal and sigmoid colon cancer.

[Meta-analysis of efficacy and safety of liver transplantation in treating cholangiocarcinoma].

OBJECTIVE: To evaluate the therapeutic efficacy and safety of liver transplantation for patients with cholangiocarcinoma. METHODS: According to the requirements of Cochrane systematic review, a thorough literature search was performed in Pubmed/Medline, Embase and Cochrane Central Register electronic databases ranged between 1995 and 2009 in terms of the key words "liver transplantation", and "cholangiocarcinoma" or "cholangiocellular carcinoma" or "bile duct cancer". And restricted the articles published in the English language. Two reviewers independently screened the studies for eligibility, evaluated the quality and extracted the data from the eligible studies with confirmation by cross-checking. Data were processed for a meta-analysis by Stata 10 software with 1-, 3-, 5-year survival rates and incidence of complications. RESULTS: A total of 14 clinical trials containing 605 patients were finally enrolled in this study. The overall 1-, 3-, 5-year pooled survival rates were 73% (95%CI: 0.65 - 0.80), 42% (95%CI: 0.33 - 0.51) and 39% (95%CI: 0.28 - 0.51), respectively. Of note, preoperative adjuvant therapies (OLT-PAT group) rendered the transplanted individuals comparably favorable outcomes with 1-, 3-, 5-year pooled survival rates of 83% (95%CI: 0.57 - 0.98), 57% (95%CI: 0.18 - 0.92) and 65% (95%CI: 0.40 - 0.87), respectively. In addition, the overall pooled incidence of complications was 62% (95%CI: 0.44 - 0.78), among which that of OLT-PAT group (58%, 95%CI: 0.20 - 0.92) was relatively acceptable compared to those of liver transplantation alone (61%, 95%CI: 0.33 - 0.85) and liver transplantation with extended bile duct resection (78%, 95%CI: 0.55 - 0.94). CONCLUSIONS: In comparison to curative resection of cholangiocarcinoma with the 5-year survival rate reported from 20% to 40%, the role of liver transplantation alone is so limited, but neoadjuvant radiochemotherapy combined with liver transplantation can bring better short- and long-term prognosis.

[Construction of a novel bioreactor of bioartificial liver system with human bone marrow mesenchymal stem cells].

OBJECTIVE: To design a novel bioreactor of bioartificial liver system by using expanded and differentiated human bone marrow mesenchymal stem cells (hBMMSCs) as active cells. METHODS: hBMMSCs were isolated from bone marrow of volunteers and grown to 10(7) population, and then replanted into hollow fiber cartridge to expand continuously for 10 days. They were incubated in differentiation medium containing recombinant human hepatocyte growth factor (rhHGF), recombinant human fibroblast growth factor 4 (rhFGF-4), recombinant human oncostatin M (rhOSM), and the cells were induced to differentiate into hepatocyte-like cells for 21 days. The functions of the differentiated cells, such as synthesis of albumin (Alb), alpha fetoprotein (AFP) were determined. Eighteen days later, the functions of metabolism of ammonia and benzodiazepines, and synthesis of urea were monitored. The cellular synthesis rate of Alb was measured with flow cytometer. The glucose levels in the medium were measured during entire culture process. RESULTS: (1)Glucose-uptake in the cartridge was increased during the culture period, and at the end of culture, the number of cells in the cartridge increased to 10(9). (2)After induction, AFP was detected on day 6, reaching the peak level on day 12. Alb was detected on day 9. Eighteen days after being induced, the clearance rate of ammonia and benzodiazepines in the cartridge was 2.0-2.7 mmol/24 hours and 3.2-3.8 mg/24 hours, respectively, and urea production rate was 1.8-2.2 mmol/24 hours. (3)At the end of the culture, 66.18%-76.91% of the cells showed positive Alb expression. CONCLUSION: hBMMSCs can be multiply to construct a novel bioreactor of bioartificial liver system in a hollow fiber cartridge.

[The prevention and treatment of post-resectional live failure for hepatocellular carcinoma].

OBJECTIVE: To investigate the cause of liver failure after hepatectomy for hepatocellular carcinoma and explore its prevention and treatment. METHODS: The clinical data of 1000 patients with hepatocellular carcinoma undergone hepatectomy from July 2000 to June 2008 were retrospectively analyzed. There were 922 male and 78 female, aging from 21 to 89 years old. RESULTS: Among the 1000 patients, there were 18 patients with liver failure after hepatectomy (1.8%). Among the 18 patients with liver failure, 13 patients were more than 65 years old, 14 patients were with more than 20% of indocyanine green retention rate at 15 minutes, 14 patients were with more than 1000 ml blood loss during operation, 6 patients were with F4/F3 liver fibrosis (Metavir Scores), and 9 patients were with less than 40.0% liver volume of residue liver. CONCLUSIONS: Patients with hepatocellular carcinoma with less than volume of residue liver, much more blood loss or transfusion, more than 20% of ICGR15, F4/F3 liver cirrhosis are prone to be with liver failure after hepatectomy. Artificial liver or liver transplantation may be the important alternative for liver failure after hepatectomy.

MUC1 promotes glycolysis through inhibiting BRCA1 expression in pancreatic cancer.

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.

The methods of preoperative biliary drainage for resectable hilar cholangiocarcinoma patients: A protocol for systematic review and meta analysis.

OBJECTIVES: To compare the clinical outcomes of endoscopic biliary drainage (EBD) with those of percutaneous transhepatic biliary drainage (PTBD) in patients with resectable hilar cholangiocarcinoma (HCCA) and evaluate the effect of EBD and PTBD on tumor prognosis. MATERIALS AND METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for articles about the comparison between PTBD and EBD. Data were analyzed by Revman 5.3. RESULTS: PTBD showed a lower risk of drainage-related complications than EBD (OR, 2.73; 95%CI, 1.52-4.91; P < .05). PTBD was also associated with lower risk of pancreatitis (OR, 8.47; 95%CI, 2.28-31.45; P < .05). The differences in preoperative cholangitis, R0 resection, blood loss and recurrence showed no statistically significance between EBD and PTBD (all P > .05). Several literatures have reported the tumor implantation metastasis after PTBD. Since no well-designed prospective randomized controlled studies have explored in this depth, this article is unable to draw conclusions on this aspect. CONCLUSION: PTBD is a reasonable choice for PBD, and EBD should only be used as preoperative drainage for HCCA by more experienced physicians. There is a greater need to design prospective randomized controlled studies to obtain high-level evidence-based medicinal proof. It is worth noting that, whether EBD or PTBD, accurate selective biliary drainage should be the trend.

Conditional loss of geranylgeranyl diphosphate synthase alleviates acute obstructive cholestatic liver injury by regulating hepatic bile acid metabolism.

Previous studies have suggested that metabolites in the mevalonate pathway are involved in hepatic bile acid metabolism, yet the details of this relationship remain unknown. In this study, we found that the hepatic farnesyl pyrophosphate (FPP) level and the ratio of FPP to geranylgeranyl pyrophosphate (GGPP) were increased in mice with acute obstructive cholestasis compared with mice that underwent a sham operation. In addition, the livers of the mice with acute obstructive cholestasis showed lower expression of geranylgeranyl diphosphate synthase (GGPPS), which synthesizes GGPP from FPP. When Ggps1 was conditionally deleted in the liver, amelioration of liver injury, as shown by downregulation of the hepatic inflammatory response and decreased hepatocellular apoptosis, was found after ligation of the common bile duct and cholecystectomy (BDLC). Subsequently, liquid chromatography/mass spectrometry analysis showed that knocking out Ggps1 decreased the levels of hepatic bile acids, including hydrophobic bile acids. Mechanistically, the disruption of Ggps1 increased the levels of hepatic FPP and its metabolite farnesol, thereby resulting in farnesoid X receptor (FXR) activation, which modulated hepatic bile acid metabolism and reduced hepatic bile acids. It was consistently indicated that digeranyl bisphosphonate, a specific inhibitor of GGPPS, and GW4064, an agonist of FXR, could also alleviate acute obstructive cholestatic liver injury in vivo. In general, GGPPS is critical for modulating acute obstructive cholestatic liver injury, and the inhibition of GGPPS ameliorates acute obstructive cholestatic liver injury by decreasing hepatic bile acids, which is possibly achieved through the activation of FXR-induced bile acid metabolism.

Risk factors for long-term prognosis of hepatocellular carcinoma patients after anatomic hepatectomy.

BACKGROUND: The risk factors for patients with major postoperative complications immediately after liver resection have been identified; however, the intermediate and long-term prognoses for these patients have yet to be determined. AIM: To evaluate the factors responsible for the long-term recurrence-free survival rate in patients with hepatocellular carcinoma (HCC) following anatomic hepatectomy. METHODS: We performed a retrospective analysis of 74 patients with HCC who underwent precise anatomic hepatectomy at our institution from January 2013 to December 2015. The observational endpoints for this study were the tumor recurrence or death of the HCC patients. The overall follow-up duration was three years. The recurrence-free survival curves were plotted by the Kaplan-Meier method and were analyzed by the log-rank test. The value of each variable for predicting prognosis was assessed via multivariate Cox proportional hazards regression analysis. RESULTS: The 1-year and 3-year recurrence-free survival rates of HCC patients were 68.92% and 55.41%, respectively, following anatomic liver resection. The results showed that the 3-year recurrence-free survival rate in HCC patients was closely related to preoperative cirrhosis, jaundice level, tumor stage, maximal tumor diameter, complications of diabetes mellitus, frequency of intraoperative hypotensive episodes, estimated blood loss (EBL), blood transfusion, fluid infusion, and postoperative infection (P < 0.1). Based on multivariate analysis, preoperative cirrhosis, tumor stage, intraoperative hypotension, and EBL were identified to be predictors of 3-year recurrence-free survival in HCC patients undergoing anatomic hepatectomy (P < 0.05). CONCLUSION: Tumor stage and preoperative cirrhosis adversely affect the recurrence-free survival rate in HCC patients following anatomic hepatectomy. The long-term recurrence-free survival rate of patients with HCC is closely related to intraoperative hypotension and EBL.

Prognostic value of precise hepatic pedicle dissection in anatomical resection for patients with hepatocellular carcinoma.

The present study aimed to investigate the long-term and perioperative outcomes of precise hepatic pedicle dissection in anatomical resection (precise AR) vs non-anatomical resection (NAR) for hepatocellular carcinoma (HCC) patients.Data from a total of 270 consecutive HCC patients who underwent curative hepatectomy were retrospectively collected. Propensity score matching (PSM) analysis was performed. The long-term outcomes of precise AR and NAR were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.The 1-, 3-, and 5-year overall survival (OS) rates were 90.3%, 76.2%, and 65.7% in the PS-precise AR group, respectively (n = 103); and 88.3%, 70.5%, and 52.0% in the PS-NAR group, respectively (n = 103) (P = .043). The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 83.4%, 63.2%, and 46.0% in the PS-precise AR group, respectively; and 75.7%, 47.4%, and 28.3% in the PS-NAR group, respectively (P = .002). Multivariate analysis showed that ICG-R15, BCLC staging, and microvascular invasion (MVI) were independent risk factors for OS; while tumor size, types of resection, surgical margin, and MVI were independent risk factors for RFS. Subgroup analysis indicated that the RFS rate was significantly better in the PS-precise AR group than in the PS-NAR group for patients with MVI and tumor size ≤5 cm.After PSM, precise hepatic pedicle dissection in AR significantly improved the recurrence-free survival rate of solitary HCC patients compared with NAR, especially in those with MVI and tumor size ≤5 cm.

The differential enhancement pattern of contrast enhanced ultrasound and magnetic resonance imaging characteristics in hepatic angiomyolipoma: 7 case reports.

OBJECTIVE: To compare the enhancement pattern of hepatic angiomyolipoma (HAML) on contrast enhanced ultrasound (CEUS) and magnetic resonance (MR). METHODS: The data of seven patients (females; age 28-52 years; mean, 42 years) with histologically proven HAMLs were retrospectively reviewed. All patients underwent CEUS and MR examination. The images were analyzed by two experienced doctors who blinded to the clinical and pathological information of cases. RESULTS: The mean diameter of the nodule was 5.7 cm (range: 3.2-10 cm). Histopathologic results revealed 4 nodules to be myomatous type and 3 nodules to be mixed type. All nodules showed hyperenhanced during arterial phase on both CEUS and MRI. During portal and delayed phase, washout was more showed on MRI (5/7, 71.4%) than on CEUS (2/7, 28.6%). CONCLUSIONS: There is discrepancy of enhancement pattern between CEUS and MRI. The quick wash-in and sustained hyperenhancement on CEUS may be helpful for the diagnosis of HAML.

Evidence for a role of geranylgeranylation in renal angiomyolipoma and renal epithelioid angiomyolipoma.

Research on mevalonate kinase deficiency has revealed that it may lead to the development of renal angiomyolipomas (RAMLs). Thus, it was suspected that geranylgeranyl pyrophosphate synthase (GGPPS), a key enzyme in the mevalonate pathway, may be involved in the development of RAMLs. In the present study, the expression of GGPPS in RAMLs and renal epithelioid angiomyolipomas (REAs) was assessed, and paraffin embedded specimens from 60 patients, including 9 cases with REA and 51 cases with RAML, were examined. Immunoreactivity was evaluated semi-quantitatively according to the intensity of staining and the percentage of positively stained cells. The results indicated that GGPPS was predominantly present in the cytoplasm, and REA tissues exhibited higher expression of GGPPS in the cytoplasm compared with RAML tissues. It was also identified that GGPPS was upregulated in TSC2-null cells, and inhibition of GGPPS could induce apoptosis of TSC2-null cells by autophagy. In conclusion, the increased expression of GGPPS in RAMLs and REAs indicated that mevalonate pathways may be involved in disease progression. GGPPS may serve as a potential therapeutic target and the current results may provide a novel therapeutic strategy for RAML and lymphangioleiomyomatosis.

HSC-specific knockdown of GGPPS alleviated CCl4-induced chronic liver fibrosis through mediating RhoA/Rock pathway.

Hepatic stellate cells (HSCs) play a critical role in the pathogenesis and reversal of liver fibrosis. Targeting HSCs is of great significance in the treatment of hepatic fibrosis, and has attracted wide attention of scholars. Here we demonstrated that expression of geranylgeranyldiphosphate synthase (GGPPS) predominantly increased in HSCs in murine fibrotic liver. HSC-specific knockdown of GGPPS using vitamin A-coupled liposome carrying siRNA-ggpps decreased activation of HSCs and alleviated fiber accumulation in vivo. Furthermore, our in vitro studies showed that GGPPS was up-regulated during HSCs activation in TGF-ß1-dependent manner. Inhibition of GGPPS suppressed TGF-ß1 induced F-actin reorganization and HSCs activation in LX-2 cells. Further, we found that GGPPS regulated HSCs activation and liver fibrosis possibly by enhancing RhoA/Rock kinase signaling. So its concluded that GGPPS promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrosis therapies.

Application of contrast enhanced ultrasound in gallbladder lesion: is it helpful to improve the diagnostic capabilities?

The aim of this study is to evaluate if contrast enhanced ultrasound (CEUS) can improve the differential diagnostic performance of gallbladder (GB) lesions. MATERIALS AND METHODS: Forty-nine patients (18 men, 31 women; mean age, 54.8±14.4 years, range age, 22-78 years) with GB lesions (mass-forming and wall-thickened types) were enrolled in this study. All patients underwent conventional ultrasonography (US) and CEUS examination. The imaging characteristics of GB lesions were analyzed to compare the diagnostic performance of US and CEUS. The final diagnosis was obtained by histopathology. RESULTS: There were significant differences between benign and malignant GB lesions with regards to size, shape, vascularity, the integrity and margin of GB wall and time to iso-enhancement on CEUS (p<0.05). However, no significant difference was found concerning the enhancement patterns between the two groups (p>0.05). Logistic regression analysis showed that the boundary between liver and GB wall (p=0.017) and vascularity on color Doppler flow imaging (p=0.013) were two independent predictors of malignancy. The diagnostic accuracy of US could be improved in combination with CEUS (65.3% vs 83.7%). The diagnostic accuracy of the GB wall thickening type was higher than the mass forming type. CONCLUSION: CEUS could improve the diagnostic performance of GB lesions, especially for wall-thickened type lesions.

Reduced triglyceride accumulation due to overactivation of farnesoid X receptor signaling contributes to impaired liver regeneration following 50% hepatectomy in extra­cholestatic liver tissue.

The aim of the present study was to investigate the role of triglyceride metabolism in the effect of obstructive cholestasis on liver regeneration following 50% partial hepatectomy (PH). Obstructive cholestatic rat models were achieved via ligation of the common bile duct (BDL). Following comparisons between hepatic pathological alterations with patients with perihilar cholangiocarcinoma, rats in the 7 day post­BDL group were selected as the BDL model for subsequent experiments. Liver weight restoration, proliferating cell nuclear antigen labeling index, cytokine and growth factor expression levels, and hepatic triglyceride content were evaluated to analyze liver regeneration post­PH within BDL and control group rats. The results of the present study revealed that obstructive cholestasis impaired liver mass restoration, which occurred via inhibition of early stage hepatocyte proliferation. In addition, reduced triglyceride content and inhibited expression of fatty acid ß­oxidation­associated genes, peroxisome proliferator activated receptor α and carnitine palmitoyltransferase, were associated with an insufficient energy supply within the BDL group post­PH. Notably, the expression levels of fatty acid synthesis­associated genes, including sterol­regulatory element­binding protein­1c, acetyl­coA carboxylase 1 and fatty acid synthase were also reduced within the BDL group, which accounted for the reduced triglyceride content and fatty acid utilization. Further investigation revealed that overactivated farnesoid X receptor (FXR) signaling may inhibit fatty acid synthesis within BDL group rats. Collectively, the role of triglycerides in liver regeneration following PH in extra­cholestatic livers was identified in the present study. Additionally, the results indicated that overactivated FXR signaling­induced triglyceride reduction is associated with insufficient energy supply and therefore contributes to the extent of impairment of liver regeneration following PH within extra­cholestatic livers.

Low-level clonal FGFR2 amplification defines a unique molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population.

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double-color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization. We further determined FGFR2 protein expression by immunohistochemistry and analyzed the clinicopathologic records of the patients. Eight tumors (6.6%) had FGFR2 translocations, whereas 15 (12.3%) had low-level FGFR2 amplification. Interestingly, the tumors that showed both translocation and low-level amplification frequently were of the mass-forming type. Compared with the ICCs with normal FGFR2s, tumors with amplifications secreted less mucus (P = .017) and typically were accompanied by hepatitis B virus infection (P = .004). Tumors with low-level amplification generally were of lower stage (P = .013) and associated with better overall survival (P = .017). As tumors with FGFR2 amplification exhibit different biology from lesions with a normal gene, low-level amplification of FGFR2 may play an important role in tumor progression and may be a marker for targeted therapy.