Angelica sinensis Polysaccharide and Astragalus membranaceus Polysaccharide Accelerate Liver Regeneration by Enhanced Glycolysis via Activation of JAK2/STAT3/HK2 Pathway.

The promotion of liver regeneration is crucial to avoid liver failure after hepatectomy. Angelica sinensis polysaccharide (ASP) and Astragalus membranaceus polysaccharide (AMP) have been identified as being associated with hepatoprotective effects. However, their roles and specific mechanisms in liver regeneration remain to be elucidated. In the present study, it suggested that the respective use of ASP or AMP strikingly promoted hepatocyte proliferation in vitro with a wide range of concentrations (from 12.5 µg/mL to 3200 µg/mL), and a stronger promoting effect was observed in combined interventions. A significantly enhanced liver/body weight ratio (4.20%) on day 7 and reduced serum transaminase (ALT 243.53 IU/L and AST 423.74 IU/L) and total bilirubin (52.61 IU/L) levels on day 3 were achieved by means of ASP-AMP administration after partial hepatectomy in mice. Metabonomics showed that differential metabolites were enriched in glycolysis with high expression of beta-d-fructose 6-phosphate and lactate, followed by significantly strengthened lactate secretion in the supernatant (0.54) and serum (0.43) normalized to control. Upon ASP-AMP treatment, the knockdown of hexokinase 2 (HK2) or inhibited glycolysis caused by 2-deoxy-d-glucose decreased hepatocyte proliferation in vitro and in vivo. Furthermore, pathway analysis predicted the role of JAK2/STAT3 pathway in ASP-AMP-regulated liver regeneration, and phosphorylation of JAK2 and STAT3 was proven to be elevated in this promoting process. Finally, downregulated expression of HK2, an attenuated level of lactate secretion, and reduced hepatocyte proliferation were displayed when STAT3 was knocked out in vitro. Therefore, it can be concluded that ASP-AMP accelerated liver regeneration and exerted a hepatoprotective effect after hepatectomy, in which the JAK2/STAT3/HK2 pathway was actively involved in activating glycolysis.

Associating liver partition and portal vein ligation for staged hepatectomy in the treatment of colorectal cancer liver metastases.

Colorectal cancer (CRC) is a common malignancy of the digestive system. Colorectal liver cancer metastasis (CRLM) occurs in approximately 50% of the patients and is the main cause of CRC mortality. Surgical resection is currently the most effective treatment for CRLM. However, given that the remnant liver volume after resection should be adequate, only a few patients are suitable for radical resection. Since Dr. Hans Schlitt first performed the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for CRLM in 2012, ALPPS has received considerable attention and has continually evolved in recent years. This review explains the technical origin of the ALPPS procedure for CRLM and evaluates its efficacy, pointing to its favorable postoperative outcomes. We also discuss the patient screening strategies and optimization of ALPPS to ensure long-term survival of patients with CRLM in whom surgery cannot be performed. Finally, further directions in both basic and clinical research regarding ALPPS have been proposed. Although ALPPS surgery is a difficult and high-risk technique, it is still worth exploration by experienced surgeons.

Triple guidance of choledochoscopy, ultrasonography, and computed tomography facilitates percutaneous catheter drainage of infected walled-off necrosis.

OBJECTIVES: Percutaneous catheter drainage (PCD) is usually performed to treat acute pancreatitis complicated by infected walled-off necrosis (WON). Insufficient drainage of infected WON may lead to a prolonged recovery process. Here, we introduce a modified PCD strategy that uses the triple guidance of choledochoscopy, ultrasonography, and computed tomography (CUC-PCD) to improve the therapeutic efficiency. METHODS: This study retrospectively analysed 73 patients with acute pancreatitis-related WON from January 2015 to January 2021. The first 38 patients were treated by ultrasonography/computed tomography-guided PCD (UC-PCD), and the next consecutive 35 patients by CUC-PCD. Perioperative data, procedural technical information, treatment outcomes, and follow-up data were collected. RESULTS: Demographic characteristics were statistically comparable between the two treatment groups (p > 0.05). After 48 h of PCD treatment, the CUC-PCD group achieved a significantly smaller size of the infected WON (p = 0.023), lower inflammatory response indexes (p = 0.020 for white blood cells, and p = 0.031 for C-reactive protein), and severity scores than the UC-PCD group (p < 0.05). Less catheter duration (p = 0.001), hospitalisation duration (p = 0.000), and global costs (p = 0.000) were observed in the CUC-PCD group compared to the UC-PCD group. There were no differences between the two groups regarding the rate of complications. CONCLUSIONS: CUC-PCD is a safe and efficient approach with potential clinical applicability for treating infected WON owing to its feasibility in placing the drainage catheter at the optimal location in real time and performing primary necrosectomy without sinus tract formation and enlargement.

Progesterone suppresses the progression of colonic carcinoma by increasing the activity of the GADD45α/JNK/c­Jun signalling pathway.

Colorectal cancer (CRC) is the third most diagnosed cancer worldwide. Progesterone is associated with a decreased risk of CRC and leads to a favourable prognosis. However, the specific mechanism by which progesterone suppresses malignant progression remains to be elucidated. In the present study, the level of progesterone was first analysed in 77 patients with CRC, and immunohistochemistry was performed to detect the expression of progesterone receptor (PGR) in the paired specimens. The correlations between progesterone, PGR and CRC prognosis were assessed. A Cell Counting Kit­8 assay was then used to detect proliferation of the CRC cells. Flow cytometry was performed to estimate apoptosis and to evaluate the cycle of the CRC cells. A xenograft tumour model was established in nude mice to assess the role of progesterone in tumour growth. Finally, a PCR microarray was used to screen differentially expressed genes to further interpret the mechanism by which progesterone inhibits the malignant progression of CRC. It was found that low expression of progesterone and PGR were significantly associated with poor prognosis of CRC. In addition, progesterone suppressed CRC cell proliferation by arresting the cell cycle and inducing apoptosis in vitro. Moreover, the inhibitory role of progesterone in tumour growth was verified in vivo. Further investigation showed that the level of growth arrest and DNA damage­inducible protein α (GADD45α) was up­regulated by progesterone, and this was followed by the activation of the JNK pathway. Progesterone increased the activity of the JNK pathway via GADD45α to inhibit proliferation by arresting the cell cycle and inducing apoptosis, thereby suppressing the malignant progression of CRC. Therefore, it can be concluded that progesterone and PGR might act as inhibiting factors for poor prognosis of CRC.

Sinusoidal Endothelial Cell Progenitor Cells Promote Tumour Progression in Patients with Hepatocellular Carcinoma.

OBJECTIVE: As sinusoidal endothelial cell progenitor cells (SEPCs) play a significant role in liver regeneration, it is necessary to elucidate whether SEPCs participate in tumour progression of hepatocellular carcinoma (HCC). METHODS: A total of 45 patients with primary HCC who underwent liver resection were included in this study. The liver tumours were removed from the patients, and partial tissues were prepared to identify SEPCs through double staining of CD133/CD45 and CD133/CD31 at the same location. Blood samples were collected to examine liver function parameters and tumour markers. The demographics and clinicopathological characteristics of the patients were collected for correlation analysis with SEPCs. RESULTS: SEPCs were observed in several blood vessels within the HCC nodules of all 45 patients, but no SEPCs were detected in the tumour-adjacent tissues. The number of SEPCs was correlated with the expression levels of HCC tumour markers α-fetoprotein (AFP) and CA199. There was a positive correlation between the expression of SEPC markers and diameter of HCC tumours in differently differentiated specimens (P < 0.01). The expression levels of SEPC markers were significantly higher in patients with poorly differentiated HCC than in patients with moderately and highly differentiated HCC (P < 0.05). CONCLUSIONS: SEPCs are closely associated with HCC progression; therefore, SEPCs may be considered potential prognostic and metastatic biomarkers and therapeutic candidates for HCC.

The bridge stenting-based internal drainage in pancreatic trauma patients with main pancreatic duct injury.

Pancreatic trauma is associated with high mortality and morbidity, especially in main pancreatic duct (MPD) injuries. Here, we introduce a novel technique via the placement of bridge stenting-based internal drainage (BSID) along the injured MPD to restore pancreatic tissue integrity. Twelve patients with MPD injury underwent unobstructed BSID as physical support for healing. Six patients with peripheral organ injuries underwent operative end-to-end anastomosis of the MPD by using a polyurethane central venous catheter for the BSID, and the other six patients with isolated proximal MPD rupture received BSID via endoscopic pancreatic stent placement. The BSID technique was successfully performed in all pancreatic trauma patients without the need for a second open surgery. With this simplified BSID-based operation, a short procedure duration (242.7 ± 38.71 min in the surgical group and 100.2 ± 16.24 min in the endoscopic group) and a short hospital stay (13.0 ± 7.05 days) were achieved. However, a few complications (41.67%) still occurred, including pancreatitis, fistula, abscess, pseudocyst, cholangitis, and haemorrhage. Except for the deceased case, all postoperative courses were marked by decreases in the peripancreatic fluid collection, blood amylase recovery, and normal endocrine function. The BSID approach is a feasible surgical approach for the treatment of MPD injury and can be used endoscopically in isolated MPD injuries for its safety and convenience.

Combined lithotripsy of mechanical clamping and electrohydraulics in facilitating endoscopic management of refractory residual biliary calculi after surgery.

Although postoperative cholangioscopy (POC) guided electrohydraulic lithotripsy (EHL) is considered to be a conventional technique for residual biliary calculi, its efficacy still needs to be improved to fit in the managemet of refractory calculi. This study evaluated the efficacy and safety of combined lithotripsy of mechanical clamping and electrohydraulics in fragmentation and removal of refractory calculi. Totally, 281 patients, who suffered from residual biliary calculi after hepatectomy and underwnet POC from August 2016 to June 2018 were involved. The first 128 patients were subjected to conventional EHL, and later consective 153 to combined lithotripsyof mechanical clamping and EHL. Perioperative data, technical information, treatment outcomes and follow-up results were collected. Clinical characteristics were statistically comparable (P > 0.05). The overall POC interventional sessions (2.0 ± 0.65 vs. 2.9 ± 1.21 sessions), average operating time (99.1 ± 34.88 vs. 128.6 ± 72.87 minutes), incidence of intraoperative hemobilia (4.58% vs. 10.93%), cholangitis (6.54% vs. 14.06%), postoperative complications (10.45% vs. 21.87%), T-tube retaining time after first POC (20.7 ± 5.35 vs. 28.1 ± 8.28 days), and treatment costs ($2375 ± 661.72 vs. $3456.7 ± 638.07) were significantly lower in the combined lithotripsy group than those in the EHL group (P < 0.05). There were no differences between the two groups in calculi recurrence at half-a year, or one year follow-up. In conclusion, combined lithotripsy of mechanical clamping and electrohydraulics can safely and effectively benefit postoperative patients along with refractory residual biliary calculi.

Activation of muscarinic acetylcholine receptor 1 promotes invasion of hepatocellular carcinoma by inducing epithelial-mesenchymal transition.

Hepatocellular carcinoma is the second leading cause of cancer-related death worldwide. Neural regulation plays an important role in the development of hepatocellular carcinoma, and activation of sympathetic nervous system can promote the migration and invasion of cancer cells. However, little research has been conducted on how the vagus nerve influences hepatocellular carcinoma. In this study, we found that the expression of vesicular acetylcholine transporter, a biomarker of vagus nerve, was associated with hepatocellular carcinoma patients' clinicopathological characteristics by immunohistochemistry. Further, activation of muscarinic acetylcholine receptor 1 (M1R) promoted HepG2 and SMMC-7721 cells migration and invasion and epithelial-mesenchymal transition via PI3K/Akt pathway. Moreover, inhibition of M1R by antagonist or shRNA suppressed hepatocellular carcinoma cells migration and invasion in vitro and in vivo, inhibited epithelial-mesenchymal transition and PI3K/Akt pathway. Therefore, these results indicate that activation of M1R promotes invasion of hepatocellular carcinoma through epithelial-mesenchymal transition and PI3K/Akt pathway.

Endoscopic dissection of refractory pancreatic duct stricture via accessory pancreatic duct approach for concurrent treatment of anomalous pancreaticobiliary junction in aging patients.

BACKGROUND: Although endoscopic management of pancreatic strictures by dilation and stenting is well established, some high-grade strictures are refractory to conventional methods. Here, we report a novel technique via accessory pancreatic duct (APD) approach to simultaneously release chronic pancreatitis-associated pancreatic stricture and correct anomalous pancreaticobiliary junction (APBJ). Due to APBJ and stricture of proximal main pancreatic duct, the APD turned out to be compensatory expansion. The stiff stenosis was dissected along the axial of APD using needle-knife electrocautery or holmium laser ablation, and then the supporting stent was placed into the pancreatic body duct. By doing so, the outflow channels of pancreatic and biliary ducts were exquisitely separated. PATIENTS AND METHODS: Two patients aged 69 and 71 years underwent stricture dissection and stent insertion for fluent drainage of pancreatic juice. The postoperative course was marked by complete abdominal pain relief and normal blood amylase recovery. In the first patient, wire-guided needle-knife electrocautery under fluoroscopic control was applied to release refractory stricture. The second patient was treated by SpyGlass pancreatoscopy-guided holmium laser ablation to lift pancreatic stricture. RESULTS: Plastic stents in APD were removed at 3 months after surgery, and magnetic resonance imaging at 6 months showed strictly normal aspect of the pancreatic duct. CONCLUSION: Although both cases were successful without severe complications, we recommend this approach only for selected patients with short refractory pancreatic strictures due to chronic pancreatitis. In order to prevent severe complications (bleeding, perforation or pancreatitis), direct-view endoscopy-guided electrotomy needs to be developed.

Routine guidewire application facilitates cholangioscopy in the management of postoperative residual hepatolithiasis.

BACKGROUND AND AIM: Although postoperative cholangioscopy (POC) is considered to be an effective treatment for residual hepatolithiasis after surgery, its security and validity still need to be improved. This study compared wire-guided POC (WG-POC) versus traditional POC (T-POC) in the management of patients with residual hepatolithiasis. METHODS: This retrospective study included a total of 203 patients who suffered from hepatolithiasis and underwent hepatectomy as initial intervention from 1 January 2016 to 1 January 2017. After surgery, 110 patients were subjected to T-POC and 93 to WG-POC for eliminating residual hepatolithiasis. Perioperative course and follow-up outcomes were retrospectively analyzed. RESULTS: No significant differences in clinical characteristics or distribution of residual hepatolithiasis between the WG-POC and T-POC groups were observed (P > 0.05). However, overall POC interventional sessions (2.9 ± 0.85 vs 4.0 ± 1.21 times), average operating time (264.8 ± 103.61 vs 389.4 ± 136.26 min), overall complications rate (18.28% vs 32.73%), and overall T-tube retaining time (21.8 ± 6.20 vs 28.8 ± 8.09 days) were lower in the WG-POC group than in the T-POC group (P < 0.05). In addition, there were no significant differences between the two groups (WG-POC vs T-POC) in recurrence (4.30% vs 4.55%) and residual calculi (8.60% vs 6.36%) at half-a-year follow up (P > 0.05). CONCLUSIONS: Routine wire guidance may improve the outcome of cholangioscopy in managing complicated residual hepatolithiasis, being associated with clear advantages such as shorter operating time and number of POC interventions, reduced T-tube retaining time, and fewer postoperative complications.

Step-by-step strategy in the management of residual hepatolithiasis using post-operative cholangioscopy.

Hepatolithiasis is the presence of calculi within the intrahepatic bile duct specifically located proximal to the confluence of the left and right hepatic ducts. The ultimate goal of hepatolithiasis treatment is the complete removal of the stone, the correction of the associated strictures and the prevention of recurrent cholangitis. Although hepatectomy could effectively achieve the above goals, it can be restricted by the risk of insufficient residual liver volume, and has a 15.6% rate of residual hepatolithiasis. With improvements in minimally invasive surgery, post-operative cholangioscopy (POC), provides an additional option for hepatolithiasis treatment with higher clearance rate and fewer severe complications. POC is very safe, and can be performed repeatedly until full patient benefit is achieved. During POC three main steps are accomplished: first, the analysis of the residual hepatolithiasis distribution indirectly by imaging methods or directly endoscopic observation; second, the establishment of the surgical pathway to relieve the strictures; and third, the removal of the stone by a combination of different techniques such as simple basket extraction, mechanical fragmentation, electrohydraulic lithotripsy or laser lithotripsy, among others. In summary, a step-by-step strategy of POC should be put forward to standardize the procedures, especially when dealing with complicated residual hepatolithiasis. This review briefly summarizes the classification, management and complications of hepatolithiasis during the POC process.

Surrogate endpoint for overall survival in assessment of adjuvant therapies after curative treatment for hepatocellular carcinoma: a re-analysis of meta-analyses of individual patients' data.

The gold standard endpoint to evaluate the effect of treatment for hepatocellular carcinoma (HCC) is overall survival (OS), but it requires a longer follow-up period to observe. This study aimed to identify whether disease-free survival (DFS) could be used as a surrogate endpoint for OS to assess the efficacy of adjuvant therapies after curative treatment (surgical resection and ablation) for HCC patients. A systematic review was conducted to identify trials about curative treatment combined with or without adjuvant therapies (interferon, IFN; or transarterial chemoembolization, TACE) for HCC. Total of 2211 patients' data from 17 trials were analyzed. At the individual study level, DFS was strongly correlated to OS (ρ = 0.988 and 0.930, 95% CI: 0.965-0.996 and 0.806-0.976 for the studies comparing Radiofrequency ablation (RFA) + TACE to RFA alone; and for the studies comparing curative treatment + IFN to curative treatment alone, respectively). At the trial level, the effects of treatment on DFS and OS were also strongly correlated to each other (R = 0.815 and 0.854, 95% CI: 0.536-0.934 and 0.621-0.948, respectively). In conclusion, DFS could be used as a potential surrogate endpoint for OS to assess the effect of adjuvant therapies after curative treatment for HCC.

HOXB7 accelerates the malignant progression of hepatocellular carcinoma by promoting stemness and epithelial-mesenchymal transition.

BACKGROUND: Homeobox B7 (HOXB7) has been identified associated with poor prognosis of hepatocellular carcinoma (HCC). However, the specific mechanism by which HOXB7 promotes the malignant progression of HCC remains to be determined. METHODS: Immunohistochemistry (IHC) was used to detect the expression level of HOXB7 in 77-paired HCC tissue samples, and the correlation between HOXB7 and HCC prognosis was assessed. The location of HOXB7 was confirmed by immunofluorescence. Cell Titer-Blue assay was used to assess the proliferation of hepatoma cells. The stem-like properties of hepatoma cells were analysed by sphere formation and clone formation assays. The effect of HOXB7 on expression of cancer stem cell markers was evaluated. Transwell and wound-healing assays were performed to estimate the invasion and migration abilities of hepatoma cells. A xenograft tumor model was established in nude mice to assess the role of HOXB7 in tumor growth. Bioluminescence imaging was used to survey the effect of HOXB7 on the metastatic ability of hepatoma cells in vivo. RESULTS: Higher expression of HOXB7 was detected in HCC tissues compared with noncancerous tissues and significantly associated with poor prognosis of HCC. In addition, HOXB7 knockdown suppressed the cell proliferation, clone formation, sphere formation, invasion and migration of hepatoma cells in vitro; conversely, these biological abilities of hepatoma cells were enhanced by HOXB7 overexpression. Moreover, the cancer stem cell markers EPCAM and NANOG were up-regulated by HOXB7. The role of HOXB7 in promoting tumor growth and metastasis was verified in vivo. Further investigation revealed that c-Myc and Slug expression was elevated by HOXB7 and the AKT pathway was activated. CONCLUSION: Overexpression of HOXB7 was significantly correlated with poor prognosis of HCC. HOXB7 up-regulated c-Myc and Slug expression via the AKT pathway to promote the acquisition of stem-like properties and facilitate epithelial-mesenchymal transition of hepatoma cells, accelerating the malignant progression of HCC.

Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells.

The sympathetic nervous system (SNS) is known to play a significant role in tumor initiation and metastasis. Hepatocellular carcinoma (HCC) frequently occurs in cirrhotic livers after chronic inflammation, and the SNS is hyperactive in advanced liver cirrhosis. However, it remains unclear whether the SNS promotes hepatocarcinogenesis by modulating chronic liver inflammation. In this study, a retrospective pathological analysis and quantification of sympathetic nerve fiber densities (tyrosine hydroxylase, TH+) in HCC patients, and diethylnitrosamine (DEN)-induced hepatocarcinogenesis in rats were performed. Our data showed that high density of sympathetic nerve fibers and α1-adrenergic receptors (ARs) of Kupffer cells (KCs) were associated with a poor prognosis of HCC. Sympathetic denervation or blocking of α1-ARs decreased DEN-induced HCC incidence and tumor development. In addition, synergistic effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-ß) in hepatocarcinogenesis were observed. The suppression of the SNS reduced IL-6 and TGF-ß expression, which suppressed hepatocarcinogenesis, and KCs play a key role in this process. After the ablation of KCs, IL-6 and TGF-ß expression and the development of HCC were inhibited. This study demonstrates that sympathetic innervation is crucial for hepatocarcinogenesis and that the SNS promotes hepatocarcinogenesis by activating α1-ARs of KCs to boost the activation of KCs and to maintain the inflammatory microenvironment. These results indicate that sympathetic denervation or α1-ARs blockage may represent novel treatment approaches for HCC.

Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients.

AIM: To investigate the efficacy and safety of adjuvant sorafenib after curative resection for patients with Barcelona Clinic Liver Cancer (BCLC)-stage C hepatocellular carcinoma (HCC). METHODS: Thirty-four HCC patients, classified as BCLC-stage C, received adjuvant sorafenib for high-risk of tumor recurrence after curative hepatectomy at a tertiary care university hospital. The study group was compared with a case-matched control group of 68 patients who received curative hepatectomy for HCC during the study period in a 1:2 ratio. RESULTS: The tumor recurrence rate was markedly lower in the sorafenib group (15/34, 44.1%) than in the control group (51/68, 75%, P = 0.002). The median disease-free survival was 12 mo in the study group and 10 mo in the control group. Tumor number more than 3, macrovascular invasion, hilar lymph nodes metastasis, and treatment with sorafenib were significant factors of disease-free survival by univariate analysis. Tumor number more than 3 and treatment with sorafenib were significant risk factors of disease-free survival by multivariate analysis in the Cox proportional hazards model. The disease-free survival and cumulative overall survival in the study group were significantly better than in the control group (P = 0.034 and 0.016, respectively). CONCLUSION: Our study verifies the potential benefit and safety of adjuvant sorafenib for both decreasing HCC recurrence and extending disease-free and overall survival rates for patients with BCLC-stage C HCC after curative resection.