Local hyperthermia mediated by gold nanoparticle-integrated silicone-covered stent: feasibility and tissue response in a rat esophageal model.

BACKGROUND: To assess the feasibility and tissue response of using a gold nanoparticle (AuNP)-integrated silicone-covered self-expandable metal stent (SEMS) for local hyperthermia in a rat esophageal model. METHODS: The study involved 42 Sprague-Dawley rats. Initially, 6 animals were subjected to near-infrared (NIR) laser irradiation (power output from 0.2 to 2.4 W) to assess the in vitro heating characteristics of the AuNP-integrated SEMS immediately after its placement. The surface temperature of the stented esophagus was then measured using an infrared thermal camera before euthanizing the animals. Subsequently, the remaining 36 animals were randomly divided into 4 groups of 9 each. Groups A and B received AuNP-integrated SEMS, while groups C and D received conventional SEMS. On day 14, groups A and C underwent NIR laser irradiation at a power output of 1.6 W for 2 min. By days 15 (3 animals per group) or 28 (6 animals per group), all groups were euthanized for gross, histological, and immunohistochemical analysis. RESULTS: Under NIR laser irradiation, the surface temperature of the stented esophagus quickly increased to a steady-state level. The surface temperature of the stented esophagus increased proportionally with power outputs, being 47.3 ± 1.4 °C (mean ± standard deviation) at 1.6 W. Only group A attained full circumferential heating through all layers, from the epithelium to the muscularis propria, demonstrating marked apoptosis in these layers without noticeable necroptosis. CONCLUSIONS: Local hyperthermia using the AuNP-integrated silicone-covered SEMS was feasible and induced cell death through apoptosis in a rat esophageal model. RELEVANCE STATEMENT: A gold nanoparticle-integrated silicone-covered self-expanding metal stent has been developed to mediate local hyperthermia. This approach holds potential for irreversibly damaging cancer cells, improving the sensitivity of cancer cells to therapies, and triggering systemic anticancer immune responses. KEY POINTS: • A gold nanoparticle-integrated silicone-covered self-expanding metal stent was placed in the rat esophagus. • Upon near-infrared laser irradiation, this stent quickly increased the temperature of the stented esophagus. • Local hyperthermia using this stent was feasible and resulted in cell death through apoptosis.

A Canine Model for Lymphangiography and Thoracic Duct Access.

OBJECTIVE: To evaluate the technical feasibility of intranodal lymphangiography and thoracic duct (TD) access in a canine model. MATERIALS AND METHODS: Five male mongrel dogs were studied. The dog was placed in the supine position, and the most prominent lymph node in the groin was accessed using a 26-gauge spinal needle under ultrasonography (US) guidance. If the cisterna chyli (CC) was not opacified by bilateral lymphangiography, the medial iliac lymph nodes were directly punctured and Lipiodol was injected. After opacification, the CC was directly punctured with a 22-gauge needle. A 0.018-in microguidewire was advanced through the CC and TD. A 4-Fr introducer and dilator were then advanced over the wire. The microguidewire was changed to a 0.035-in guidewire, and this was advanced into the left subclavian vein through the terminal valve of the TD. Retrograde TD access was performed using a snare kit. RESULTS: US-guided lymphangiography (including intranodal injection of Lipiodol [Guerbet]) was successful in all five dogs. However, in three of the five dogs (60%), the medial iliac lymph nodes were not fully opacified due to overt Lipiodol extravasation at the initial injection site. In these dogs, contralateral superficial inguinal intranodal injection was performed. However, two of these three dogs subsequently underwent direct medial iliac lymph node puncture under fluoroscopy guidance to deliver additional Lipiodol into the lymphatic system. Transabdominal CC puncture and cannulation with a 4-Fr introducer was successful in all five dogs. Transvenous retrograde catheterization of the TD (performed using a snare kit) was also successful in all five dogs. CONCLUSION: A canine model may be appropriate for intranodal lymphangiography and TD access. Most lymphatic intervention techniques can be performed in a canine using the same instruments that are employed in a clinical setting.

Ginsenoside Rg3 Decreases NHE1 Expression via Inhibiting EGF-EGFR-ERK1/2-HIF-1 α Pathway in Hepatocellular Carcinoma: A Novel Antitumor Mechanism.

Na + /H + exchanger 1 (NHE1) plays a vital role in the oncogenesis and development of hepatocellular carcinoma (HCC) and has been regarded as a promising target for the treatment of HCC. Ginsenoside Rg3 (Rg3), a bioactive ginseng compound, is suggested to possess pleiotropic antitumor effects on HCC. However, the underlying mechanisms of Rg3 suppressing HCC remain unclear. In the present study, we uncovered a novel antitumor mechanism of Rg3 on HCC by decreasing NHE1 expression through in vivo and in vitro studies. Mechanistically, we demonstrated that epidermal growth factor (EGF) could dramatically upregulate NHE1 expression, while increasing the phosphorylated extracellular signal-regulated protein kinase (ERK1/2) level and hypoxia-inducible factor 1 alpha (HIF-1 α) expression. In the presence of ERK1/2-specific inhibitor PD98059, EGF stimulated HIF-1 α and NHE1 expression was obviously blocked in addition, the presence of HIF-1 α -specific inhibitor 2-methoxyestradiol (2-MeOE2) blocked EGF stimulated NHE1 expression. Moreover, results from in vivo and in vitro studies indicate that Rg3 treatment markedly decreased the expression of EGF, EGF receptor (EGFR), phosphorylated ERK1/2 and HIF-1 α . Conclusively, these findings suggested that NHE1 was stimulated by EGF, and Rg3 could decrease NHE1 expression by integrally inhibiting EGF-EGFR-ERK1/2-HIF- α signal axis in HCC. Together, our evidence indicated that Rg3 was an effective multi-targets antitumor agent for the treatment of HCC.

EW-7197, an oral transforming growth factor ß type I receptor kinase inhibitor, for preventing peritoneal adhesion formation in a rat model.

BACKGROUND: EW-7197 is an oral transforming growth factor ß type I receptor kinase inhibitor currently undergoing phase I clinical trials for cancer treatment in the United States. This study evaluates whether EW-7197 prevents peritoneal adhesion formation in a rat model. METHODS: Forty-eight female Wistar rats underwent peritoneal adhesion induction by the creation of peritoneal ischemic buttons and were randomly divided into 4 groups of 12 each. The control group received 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The 10 mg and 20 mg groups received 10 or 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction. The rebound group received 20 mg/kg EW-7197 phosphate dissolved in 0.3 mL vehicle by oral gavage once daily for 7 days after adhesion induction followed by 0.3 mL vehicle only by gavage once daily for an additional 21 days. After the respective treatments were completed, the animals were euthanized. RESULTS: All rats survived until the end of the study without complications. EW-7197 reduced the incidence, quality, and tenacity of peritoneal adhesions in a dose-dependent manner. Fibrosis and collagen production were reduced in EW-7197-treated peritoneal ischemic buttons. Transforming growth factor ß/Smad2/3 signaling and mesothelial-to-mesenchymal transition were inhibited in EW-7197-treated peritoneal ischemic buttons. Discontinuation of EW-7197 was not associated with rebound effects. CONCLUSION: EW-7197 prevented peritoneal adhesion formation potentially via inhibition of transforming growth factor ß1/Smad2/3-induced mesothelial-to-mesenchymal transition in a rat model.

Nanofunctionalized Stent-Mediated Local Heat Treatment for the Suppression of Stent-Induced Tissue Hyperplasia.

Current therapeutic strategies are insufficient for suppressing stent-induced restenosis. Here, branched gold nanoparticles (BGNP)-coated self-expandable metallic stents (SEMSs) were developed for a local heat-induced suppression of stent-related tissue hyperplasia. Our polydopamine (PDA) coating on SEMS allowed BGNP crystal growth on the surface of SEMSs. The prepared BGNP-coated SEMS showed effective local heating under near-infrared laser irradiation. The effectiveness of BGNP-coated SEMSs for suppressing stent-related tissue hyperplasia was demonstrated in a rat esophageal model ( n = 52). BGNP-coated SEMS placement under fluoroscopic guidance was technically successful in all rats. The placed BGNP-coated SEMS in rat esophagus achieved three different local heat dose ranges (50, 65, and 80 °C) under fluoroscopic image-guided local irradiation. Follow-up endoscopic examination readily monitored the local heating and observed significantly decreased tissue hyperplasia at 4 weeks of local heat treatments (50 and 65 °C). Finally, Western blot, histology, immunohistochemistry (HSP70, αSMA, and TUNEL), and immunofluorescence (Ki67 and BrdU) analyses along with the statistical analysis confirmed that optimized BGNP-coated SEMS-mediated local heat treatments inducing the expression of anti-inflammatory HSP70 effectively suppresses tissue hyperplasia after stent placement in the esophagus. Our local heating with nanofunctionalized stents represents a promising new approach for suppressing stent-related tissue hyperplasia.

Developmental endothelial locus-1 prevents development of peritoneal adhesions in mice.

Postoperative peritoneal adhesions, fibrous bands formed in the peritoneal cavity following surgery, represent a common, challenging and costly problem faced by surgeons and patients, for which effective therapeutic options are lacking. Since aberrant inflammation is one of the key mechanisms underlying peritoneal adhesion formation, here we set out to study the role of developmental endothelial locus-1 (Del-1), which has been recently identified as an endogenous inhibitor of inflammation, in the formation of postoperative peritoneal adhesions using a mouse model of peritoneal adhesions induced by ischemic buttons. Del-1-deficient mice had a higher incidence of adhesions, and their adhesions had higher quality and tenacity scores. Del-1 deficiency also led to enhanced inflammation mediators and collagen production. Finally, Del-1 supplementation decreased the incidence and severity of postoperative peritoneal adhesions. Taken together, these results indicate a protective role for Del-1 in postoperative peritoneal adhesion formation.

Repeated transcatheter arterial chemoembolization is safe for hepatocellular carcinoma in cirrhotic patients with transjugular intrahepatic portosystemic shunt.

PURPOSE: We aimed to investigate the safety and long-term outcomes of repeated transcatheter arterial chemoembolization (TACE) in cirrhotic patients with transjugular intrahepatic portosystemic shunt (TIPS). METHODS: Data of patients with hepatocellular carcinoma, who had previous TIPS implantation and received TACE between January 2010 and December 2012, were reviewed retrospectively. The primary outcome measure was liver function, which was represented by model for end-stage liver disease score, Child-Pugh-Turcotte score, serum total bilirubin, alanine aminotransferase, and aspartate aminotransferase. Changes in liver function before and after the initial TACE procedure and hepatobiliary severe adverse events (SAEs) were compared. Liver function following the initial TACE session was compared with that obtained in later TACE sessions. The secondary outcome measures were tumor response to multiple TACE sessions and survival. RESULTS: Seventeen patients underwent at least two TACE sessions, while nine patients underwent at least three sessions during the follow-up period. There was no statistically significant difference between the liver function tests performed before and one-month after the TACE procedure. Grade 3 or 4 SAEs occurred in six (31.6 %) patients within one month. The one, two-, and three-year survival rates were 88%, 53%, and 32%, respectively. Tumor response of multiple TACE sessions was the only predictive risk factor of mortality (OR=4.40; P = 0.030; 95% CI, 1.15-16.85). CONCLUSION: Our results suggest that repeated TACE is safe in selected patients with TIPS.