Intrahepatic cholangiocarcinoma is a rare malignant biliary neoplasm that causes a poor prognosis even after curative hepatectomy. Liver metastasis is the major recurrence pattern of intrahepatic ...cholangiocarcinoma; therefore, the prevention of liver metastasis is a desirable objective. The aim of this study is to identify gene(s) related to liver metastasis of intrahepatic cholangiocarcinoma and to examine the inhibitory effects on metastasis of intrahepatic cholangiocarcinoma by controlling such gene(s). We collected 3 pairs of intrahepatic cholangiocarcinoma frozen samples, and 36 pairs (primary and metastatic lesions) of intrahepatic cholangiocarcinoma formalin‐fixed paraffin‐embedded samples, from patients who underwent surgical resection at hospitals related to the Kyushu Study Group of Liver Surgery between 2002 and 2016. We carried out cDNA microarray analyses and immunohistochemistry to identify candidate genes, and evaluated one of them as a therapeutic target using human cholangiocarcinoma cell lines. We identified 4 genes related to liver metastasis using cDNA microarray, and found that CXCL12 was the only gene whose expression was significantly higher in liver metastasis than in primary intrahepatic cholangiocarcinoma by immunohistochemistry (P = .003). In prognosis, patients in the high CXCL12 group showed a significantly poor prognosis in disease‐free (P < .0001) and overall survival (P = .0004). By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines. Therefore, CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.
CXCL12 was significantly more highly expressed in liver metastasis than in primary intrahepatic cholangiocarcinoma. In terms of prognosis, patients in the high CXCL12 group showed a significantly poorer prognosis in disease‐free and overall survival than those in the low CXCL12 group. CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.
BACKGROUNDPosttransplant liver steatosis occurs frequently and can affect patient outcome. Our aim was to clarify the risk factors for steatosis or steatohepatitis after living donor liver ...transplantation (LT) through a retrospective examination of recent 100 living donor LT recipients and their liver donors.
METHODSLiver biopsy was performed at 1 year after LT and each year, thereafter, or as needed due to abnormal liver enzyme levels, with a median follow-up of 4 years (2-10 years).
RESULTSLiver steatosis (≥5%) was identified in 33 cases, with steatohepatitis identified in 9 of 33 patients with liver steatosis. Recipients with liver steatosis were younger than those without steatosis (53.4 ± 9.5 years vs 57.6 ± 9.9 years, respectively; P = 0.045). Of note, the prevalence of steatosis was significantly higher among LT recipients who received a graft from a donor with steatosis than without (60% vs 23%, respectively; P = 0.001). Donor steatosis was also associated with steatohepatitis in recipients after LT (steatohepatitis/simple steatosis, 88%:50%). On multivariate analysis, younger recipient age (P = 0.023) and donor steatosis (P = 0.005) were independent risk factors of liver steatosis after LT. Among the 33 recipients in our study group, 26 were assessed by serial liver biopsies, with 6 showing progression of the nonalcoholic fatty liver disease activity score. An increase in body weight was predictive of steatosis progression after LT (P = 0.005).
CONCLUSIONSAge and donor steatosis influence the risk of liver steatosis and steatohepatitis in recipients after LT. The clinical course of steatosis is relatively benign, with only 19% developing nonalcoholic fatty liver disease activity score and 7.6% significant fibrosis.
The integration of a bile drainage structure into engineered liver tissues is an important issue in the advancement of liver regenerative medicine. Primary biliary cells, which play a vital role in ...bile metabolite accumulation, are challenging to obtain in vitro because of their low density in the liver. In contrast, large amounts of purified hepatocytes can be easily acquired from rodents. The in vitro chemically induced liver progenitors (CLiPs) from primary mature hepatocytes offer a platform to produce biliary cells abundantly. Here, we generated a functional CLiP‐derived tubular bile duct‐like structure using the chemical conversion technology. We obtained an integrated tubule‐hepatocyte tissue via the direct coculture of hepatocytes on the established tubular biliary‐duct‐like structure. This integrated tubule‐hepatocyte tissue was able to transport the bile, as quantified by the cholyl‐lysyl‐fluorescein assay, which was not observed in the un‐cocultured structure or in the biliary cell monolayer. Furthermore, this in vitro integrated tubule‐hepatocyte tissue exhibited an upregulation of hepatic marker genes. Together, these findings demonstrated the efficiency of the CLiP‐derived tubular biliary‐duct‐like structures regarding the accumulation and transport of bile.
The integration of a bile drainage system into engineered liver tissue was successfully performed via the direct coculture of hepatocytes on the chemically induced liver progenitors (CLiPs)‐derived tubular biliary‐duct‐like structure. The integrated tubule‐hepatocyte tissue was able to transport the bile, as quantified by the Cholyl‐Lysyl‐Fluorescein (CLF) assay. These results were highlighting the possibility of the establishment of a system that supports the interaction between the hepatocytes and the biliary‐duct‐like structure for the accumulation of the bile acid analog in vitro.
Regenerative medicine for the esophagus Kanetaka, Kengo; Kobayashi, Shinichiro; Eguchi, Susumu
Surgery today (Tokyo, Japan),
08/2018, Letnik:
48, Številka:
8
Journal Article
Recenzirano
Advances in tissue engineering techniques have made it possible to use human cells as biological material. This has enabled pharmacological studies to be conducted to investigate drug effects and ...toxicity, to clarify the mechanisms underlying diseases, and to elucidate how they compensate for impaired organ function. Many researchers have tried to construct artificial organs using these techniques, but none has succeeded in growing a whole organ. Unlike other digestive organs with complicated functions, such as the processing and absorption of nutrients, the esophagus has the relatively simple function of transporting content, which can be replicated easily by a substitute. In regenerative medicine, various combinations of materials have been applied, including scaffolding, cell sources, and bioreactors. Exciting results of tissue engineering techniques for the esophagus have been reported. In animal models, replacing full-thickness and full-circumferential defects remains challenging because of stenosis and leakage after implantation. Although many reports have manipulated various scaffolds, most have emphasized the importance of both epithelial and mesenchymal cells for the prevention of stenosis. However, the results of repair of partial full-thickness defects and mucosal defects have been promising. Two successful approaches for the replacement of mucosal defects in a clinical setting have been reported, although in contrast to the many animal models, there are few pilot studies in humans. We review the recent results and evaluate the future of regenerative medicine for the esophagus.
Liver transplantation, the only proven treatment for end‐stage liver disease and acute liver failure, is hampered by the scarcity of donors. Regenerative medicine provides an alternative therapeutic ...approach. Tremendous efforts dedicated to liver regenerative medicine include the delivery of transplantable cells, microtissues, and bioengineered whole livers via tissue engineering and the maintenance of partial liver function via extracorporeal support. This brief review summarizes the current status of regenerative medicine for the hepatobiliary system. For liver regenerative medicine, the focus is on strategies for expansion of transplantable hepatocytes, generation of hepatocyte‐like cells, and therapeutic potential of engineered tissues in liver disease models. For biliary regenerative medicine, the discussion concentrates on the methods for generation of cholangiocyte‐like cells and strategies in the treatment of biliary disease. Significant advances have been made in large‐scale and long‐term expansion of liver cells. The development of tissue engineering and stem cell induction technology holds great promise for the future treatment of hepatobiliary diseases. The application of regenerative medicine in liver still lacks extensive animal experiments. Therefore, a large number of preclinical studies are necessary to provide sufficient evidence for their therapeutic effectiveness. Much remains to be done for the treatment of hepatobiliary diseases with regenerative medicine.
Highlight
Huang and colleagues summarized the current status of regenerative medicine research on the liver and bile ducts, covering stem cell culture techniques, small molecule cocktail medium, and tissue engineering. Although there are still many challenges, the development of these technologies holds great promise for the future treatment of hepatobiliary diseases.
Objective:
To evaluate the efficacy of neuromuscular electrical stimulation on quadriceps muscle strength and thickness in liver transplantation patients.
Design:
Phase-II, randomized, ...parallel-group, allocation-concealed, assessor-blinded, single-center controlled trial.
Setting:
Inpatient rehabilitation sector.
Subjects:
Patients following living donor liver transplantation.
Interventions:
The quadriceps muscle stimulation and the control groups received bilateral muscle electrical stimulation on the quadriceps and tibialis anterior muscles, respectively. Neuromuscular electrical stimulation sessions in both groups were conducted for 30 minutes per session, once per day for five weekdays over four weeks by a physical therapist.
Main measures:
Quadriceps muscle strength and quadriceps muscle thickness.
Results:
Neuromuscular electrical stimulation was applied to the quadriceps muscles group (n = 23) or the tibialis anterior muscle in the control group (n = 22). The decrease in quadriceps muscle thickness differed significantly between both groups on postoperative day 30 (median −3 vs −8, P < 0.01). The changes in predicted quadriceps strength and 6 minutes walking distance were not significantly different between groups (quadriceps strength median −12% vs −5%, P = 0.40; 6 minutes walking distance median −18 vs −21 m, P = 0.74).
Conclusion:
Neuromuscular electrical stimulation of the quadriceps muscle for liver transplantation recipients was able to maintain the quadriceps muscle thickness after surgery. Future larger scale studies are needed to consider the effectiveness of neuromuscular electrical stimulation and how to incorporate this intervention in the overall strategy of the physical therapy program.
Aim
In human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected patients, the progression of liver failure is reported to be more aggressive than that in HCV mono‐infected patients. ...Wisteria floribunda agglutinin‐positive human Mac‐2‐binding protein (WFA+‐M2BP) is well recognized as a liver fibrosis glycobiomarker with a unique fibrosis‐related glycoalteration. We analyzed HIV/HCV coinfected patients’ M2BP levels as a possible marker for predicting liver fibrosis.
Methods
M2BP was measured in 31 HIV/HCV coinfected patients, and we analyzed the correlation between WFA+‐M2BP and several markers of fibrosis, liver function, and tumor markers. We compared the WFA+‐M2BP levels in HIV/HCV coinfected patients with those of HCV mono‐infected patients by performing a propensity score matching analysis.
Results
In the HIV/HCV coinfected patients, the serum level of WFA+‐M2BP was well correlated with the markers type IV collagen, hyaluronic acid, and alpha‐fetoprotein, but not protein induced by vitamin K absence‐II. In the propensity score matching with HCV mono‐infected patients, the WFA+‐M2BP levels were significantly higher in the HIV/HCV coinfected patients compared with the levels in the HCV mono‐infected patients.
Conclusion
In conclusion, WFA+‐M2BP might be a feasible predictive marker of fibrosis in HIV/HCV coinfected patients.
Background
The prognosis of intrahepatic cholangiocarcinoma (ICC) is based on tumor localization; however, the mechanism remains unknown. Therefore, we investigated the biological characteristics of ...perihilar and peripheral ICC in a mouse model.
Methods
The model was established by the administration of three oncogenic plasmids harboring myristoylated AKT, mutated human YAP, and pCMV‐Sleeping Beauty into the mice. The perihilar and peripheral ICC tumors that developed in the same mouse were assessed for the expression of cell adhesion factors and driver genes with immunohistochemistry and reverse transcription polymerase chain reaction (RT‐PCR).
Results
The perihilar ICC tumors were irregularly shaped, whereas the peripheral tumors were mostly circular, similar to the differences found in patients. Alpha‐smooth muscle actin was strongly expressed in the perihilar tumors at 10 weeks, and vimentin expression was significantly up‐regulated in the perihilar ICC at 14 weeks. Fgfr2 level significantly increased in peripheral ICC at 10 weeks, whereas Idh2 expression was up‐regulated in perihilar ICC.
Conclusions
Despite diffuse injection of oncogenic plasmid, expression of driver genes and oncogenes in ICC tumor cells differs depending on the tumor localization, resulting in changes in epithelial‐mesenchymal transition, which may explain the different outcomes of patients with peripheral and perihilar ICC.
Highlight
Adachi and colleagues investigated differences between the perihilar and peripheral tumor locations of intrahepatic cholangiocarcinoma (ICC) in an experimental mouse model. There were no significant differences in epithelial‐mesenchymal transition‐related proteins, but driver gene expression levels of Fgfr2 significantly increased in peripheral ICC, whereas Idh2 expression was up‐regulated in perihilar ICC.
Background
Postoperative complications related to gastric conduit reconstruction are still common issues after McKeown esophagectomy. A novel endoscopic mucosal ischemic index is desired to predict ...anastomotic complications after McKeown esophagectomy.
Aims and methods
The purpose of this study was to prospectively evaluate the safety and efficacy of endoscopic examinations of the anastomotic region in the acute period after esophagectomy.
Endoscopic examinations were performed on postoperative days (PODs) 1 and 8. The severity of ischemia was prospectively validated according to the endoscopic mucosal ischemic index (EMII).
Results
A total of 58 patients were included after evaluating the safety and feasibility of the endoscopic examination on POD 1 in 10 patients. Anastomotic leakage occurred in 6 patients. Stricture occurred in 13 patients. A greater than 67% circumference and lesion length greater than 20 mm of anastomotic ischemic area (AIA) on POD 1 were associated with developing anastomotic leakage after esophagectomy (OR: 14.5; 95% CI: 1.8–306.5;
P
= 0.03, OR: 19.4; 95% CI: 1.7–536.8;
P
= 0.03). More than 67% circumferential ischemic mucosa and ischemic mucosal lengths greater than 20 mm of AIA on POD 1 were associated with developing anastomotic strictures after esophagectomy (OR: 6.4; 95% CI: 1.4–31.7;
P
= 0.02, OR: 5.9; 95% CI: 1.2–33.1;
P
= 0.03). Patients with either more than 67% circumferential ischemic mucosa or ischemic mucosal lengths greater than 20 mm of AIA on POD 1 were defined as EMII-positive patients. The sensitivity, specificity, and positive and negative predictive values of EMII positivity on POD 1 for leakage were 100%, 78.8%, 35.3%, and 100%, respectively. The sensitivity, specificity, and positive and negative predictive values of the EMII positivity on POD 1 for strictures were 69.2%, 82.2%, 52.9%, and 90.2%, respectively.
Conclusions
The application of an endoscopic classification system to mucosal ischemia after McKeown esophagectomy is both appropriate and satisfactory in predicting anastomotic complications.
Trial registration
Clinical Trial.gov Registry, ID: NCT02937389, Registration date: Oct 17, 2015.
Ectopic liver tissue is a rare developmental anomaly that is not directly connected to the liver. We encountered ectopic liver tissue on the surface of the gallbladder wall during laparoscopic ...cholecystectomy. It has vasculature arising from the liver parenchyma and is classified according to its branching pattern. Ectopic liver tissue has been reported to occur in a variety of locations, and when encountered in surgery, it is clinically important to identify ectopic liver tissue with vascular supply to prevent unexpected bleeding. Ectopic liver tissue should be resected and examined histologically for the potential for malignancy when detected during surgical intervention.
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