Preparation of multifunctional nanobubbles and their application in bimodal imaging and targeted combination therapy of early pancreatic cancer.

Pancreatic cancer will gradually become the second leading cause of cancer death due to its poor suitability for surgical treatment, frequent recurrence and metastasis, and insensitivity to radiotherapy and chemotherapy. Strategies for precise early detection and effective targeted treatment of pancreatic cancer are urgently needed. Because of its unique advantages, molecular targeted contrast-enhanced ultrasound imaging (CEUI) has generated new opportunities to overcome this challenge. The aim of this study was to explore multifunctional nanobubbles named IR780-NBs-DTX as novel ultrasound contrast agents (UCAs) for dual-mode targeted imaging and photothermal ablation combined with chemotherapy for pancreatic cancer. An optimized "film hydration method" was used to prepare IR780-NBs-DTX in this research. The characteristics and ability of the new UCAs were detected via in vitro, in vivo and ex vivo experiments. The initial dose of 0.15 mg IR-780 iodide/1.0 mg DTX was considered to be the best formula for IR780-NBs-DTX, and the concentration of 6 ×106 bubbles/mL was best for CEUI. The excellent characteristics of IR780-NBs-DTX, including a uniform nanoscale particle size (349.8± 159.1 nm, n= 3), good performance in dual-mode imaging, high stability and reliable biocompatibility, were also proven. In the in vitro cell experiments, IR780-NBs-DTX targeted more pancreatic cancer cells than the control treatments, and the targeting rate was approximately 95.6± 1.7%. Under irradiation with an 808 nm laser, most cells died. Furthermore, the in vivo study demonstrated that IR780-NBs-DTX could precisely detect pancreatic cancer through near infrared fluorescence (NIRF) imaging and CEUI, and the tumor almost disappeared at 18 days after combined treatment. In ex vivo experiments, immunohistochemistry (IHC) and immunofluorescence (IF) showed that the expression of HSP70 increased and that of PCNA decreased, and many apoptotic tumor cells were observed by TUNEL staining in the IR780-NBs-DTX group. The newly prepared IR780-NBs-DTX are novel nanosized UCAs with high efficiency for dual-mode molecular targeted imaging and combined therapy, and they may have future potential applications in the precise detection and effective targeted therapy of small and metastatic lesions in the early stage of pancreatic cancer.

A new strategy for accurate targeted diagnosis and treatment of cutaneous malignant melanoma: dual-mode phase-change lipid nanodroplets as ultrasound contrast agents.

BACKGROUND: Currently, effective detection and treatment of cutaneous malignant melanoma (CMM) still face severe challenges. Ultrasound molecular imaging as a noninvasive and easy-to-operate method is expected to bring improvements for tumor detection. PURPOSE: The aim of this research is to prepare novel phase-change ultrasound contrast agents, Nds-IR780, which can perform not only dual-mode molecule-targeted imaging but also targeted photothermal therapy for CMM. METHODS: A double emulsion process was used to prepare the Nds-IR780. Then, the entrapment rate and drug loading of IR-780 iodide in Nds-IR780 were detected by high-performance liquid chromatography. The biocompatibility of Nds-IR780 was evaluated by a CCK-8 assay and the characteristics and stability of that were verified through the particle size analyzer, laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM). The abilities of dual-mode molecule-targeted imaging and targeted photothermal therapy for Nds-IR780 were confirmed via the in vitro and in vivo experiments. RESULTS: Nds-IR780 had good size distribution, polydispersity index, stability and biosafety. The in vitro and in vivo experiments confirmed that Nds-IR780 were capable of targeting CMM cells with high affinity (22.4±3.2%) and facilitating dual-mode imaging to detect the primary lesion and sentinel lymph nodes (SLNs) of CMM. Furthermore, the photothermal ablation of CMM mediated by Nds-IR780 was very effective in vivo. CONCLUSION: The newly prepared Nds-IR780 were observed to be effective targeted theranostic probe for the precise detection and targeted treatment of CMM.

Incidence of portal vein thrombosis after splenectomy and its influence on transjugular intrahepatic portosystemic shunt stent patency.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is widely accepted as an alternative to surgery for management of complications of portal hypertension. TIPS has been used to treat portal vein thrombosis (PVT) in many centers since the 1990s. Although TIPS has good therapeutic effects on the formation of PVT, the effect of PVT on TIPS stenting has rarely been reported. Patients with splenectomy and pericardial devascu-larization have a high incidence of PVT, which can markedly affect TIPS stent patency and increase the risk of recurrent symptoms associated with shunt stenosis or occlusion. AIM: To investigate the incidence of PVT after splenectomy and its influence on the patency rate of TIPS in patients with cirrhosis and portal hypertension. METHODS: Four hundred and eighty-six patients with portal hypertension for refractory ascites and/or variceal bleeding who required TIPS placement between January 2010 and January 2016 were included in this retrospective analysis. Patients without prior splenectomy were defined as group A (n = 289) and those with prior splenectomy as group B (n = 197). The incidence of PVT before TIPS was compared between the two groups. After TIPS placement, primary patency rate was compared using Kaplan-Meier analysis at 3, 6, 9 and 12 mo, and 2 and 3 years. The clinical outcomes were analyzed. RESULTS: Before TIPS procedure, the incidence of PVT in group A was lower than in group B (P = 0.003), and TIPS technical success rate in group A was higher than in group B (P = 0.016). The primary patency rate in group A tended to be higher than in group B at 3, 6, 9 and 12 mo, 2 years and 3 years (P = 0.006, P = 0.011, P = 0.023, P = 0.032, P = 0.037 and P = 0.028, respectively). Recurrence of bleeding and ascites rate in group A was lower than in group B at 3 mo (P ≤ 0.001 and P = 0.001), 6 mo (P = 0.003 and P = 0.005), 9 mo (P = 0.005 and P = 0.012), 12 mo (P = 0.008 and P = 0.024), 2 years (P = 0.011 and P = 0.018) and 3 years (P = 0.016 and P = 0.017), respectively. During 3-years follow-up, the 1-, 2- and 3-year survival rate in group A were higher than in group B (P = 0.008, P = 0.021, P = 0.018, respectively), but there was no difference of the incidence of hepatic encephalopathy (P = 0.527). CONCLUSION: Patients with prior splenectomy have a high incidence of PVT, which potentially increases the risk of recurrent symptoms associated with shunt stenosis or occlusion.

Safety and efficacy of transjugular intrahepatic portosystemic shunt combined with palliative treatment in patients with hepatocellular carcinoma.

BACKGROUND: There is a close relationship between cirrhosis and hepatocellular carcinoma (HCC). Transjugular intrahepatic portosystemic shunt (TIPS) has good clinical effect in treating the complication of portal hypertension. However, because of the risk of postoperative liver failure, severe complications, and low survival rate for HCC, TIPS is contraindicated in patients with portal hypertension and liver cancer. We studied a large cohort of patients with cirrhosis and HCC who underwent TIPS for recurrent variceal bleeding and/or ascites. AIM: To assess the safety, efficacy, and survival rate in patients with HCC who underwent TIPS. METHODS: Group A comprised 217 patients with HCC and portal hypertension who underwent the TIPS procedure between 1999 and 2014. After TIPS deployment, these patients received palliative treatment for HCC. Group B comprised a cohort of 136 HCC patients with portal hypertension who did not undergo TIPS placement. Group B received palliative treatment for HCC plus medical therapy for portal hypertension. The clinical outcomes and survival rate were assessed. RESULTS: In Group A, the primary technical success rate was 97.69% for TIPS placement, and no severe procedure-related complications of TIPS placement were reported. The control of variceal bleeding (VB) within 1 mo did not differ significantly between the groups (P = 0.261). Absorption of refractory ascites within 1 mo, recurrence of VB, and recurrence of refractory ascites differed significantly between the groups (P = 0.017, 0.023, and 0.009, respectively). By comparison, the rate of hepatic encephalopathy in Group B was lower than that in Group A (P = 0.036). The 1-, 2-, 3-, 4-, and 5-year survival rates were significantly different between Groups A and B (χ2 = 12.227, P = 0.018; χ2 = 12.457, P = 0.014; χ2 = 26.490, P = 0.013; χ2 = 21.956, P = 0.009, and χ2 = 24.596, P = 0.006, respectively). The mean survival time was 43.7 mo in Group A and 31.8 mo in Group B. Median survival time was 50.0 mo in Group A and 33.0 mo in Group B. Mean and median survival differed significantly between the two groups (P = 0.000, χ2 = 35.605, log-rank test). The mortality rate from VB in Group A was low than that in Group B (P = 0.006), but the rates of hepatic tumor, hepatic failure, and multiorgan failure did not differ significantly between the two groups (P = 0.173, 0.246 and 0.257, respectively). CONCLUSION: TIPS combined with palliative treatment is safe and effective for portal hypertension in patients with HCC.

Targeted puncture of left branch of intrahepatic portal vein in transjugular intrahepatic portosystemic shunt to reduce hepatic encephalopathy.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is currently used for the treatment of complications of portal hypertension. The incidence of hepatic encephalopathy (HE) remains a problem in TIPS placement. It has been reported that the right branch mainly receives superior mesenteric venous blood while the left branch mainly receives blood from the splenic vein. We hypothesized that targeted puncture of the left portal vein would divert the non-nutritive blood from the splenic vein into the TIPS shunt; therefore, targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE. AIM: To evaluate the influence of targeted puncture of left branch of portal vein in TIPS on HE. METHODS: A retrospective analysis of 1244 patients with portal-hypertension-related complications of refractory ascites or variceal bleeding who underwent TIPS from January 2000 to January 2013 was performed. Patients were divided into group A (targeting left branch of portal vein, n = 937) and group B (targeting right branch of portal vein, n = 307). TIPS-related HE and clinical outcomes were analyzed. RESULTS: The symptoms of ascites and variceal bleeding disappeared within a short time. By the endpoint of follow-up, recurrent bleeding and ascites did not differ significantly between groups A and B (P = 0.278, P = 0.561, respectively). Incidence of HE differed significantly between groups A and B at 1 mo (14.94% vs 36.80%, χ 2 = 4.839, P = 0.028), 3 mo (12.48% vs 34.20%, χ 2 = 5.054, P = 0.025), 6 mo (10.03% vs 32.24%, χ 2 = 6.560, P = 0.010), 9 mo (9.17% vs 31.27%, χ 2 = 5.357, P = 0.021), and 12 mo (8.21% vs 28.01, χ 2 = 3.848, P = 0.051). There were no significant differences between groups A and B at 3 years (6.61% vs 7.16%, χ 2 = 1.204, P = 0.272) and 5 years (5.01% vs 6.18%, χ 2 = 0.072, P = 0.562). The total survival rate did not differ between groups A and B (χ 2 = 0.226, P = 0.634, log-rank test). CONCLUSION: Targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE but has no direct influence on prognosis of portal-hypertension-related complications.

Direct Intrahepatic Portocaval Shunt for Sinusoidal Obstruction Syndrome Associated with Hepatotoxicity of Pyrrolizidine Alkaloids.

We retrospectively identified 89 consecutive patients from January 2004 to January 2012 to investigate efficacy of direct intrahepatic portocaval shunt (DIPS) combined with inferior vena cava (IVC) stenting for sinusoidal obstruction syndrome (SOS) associated with hepatotoxicity of pyrrolizidine alkaloids. Indications for treatment were variceal hemorrhage and/or refractory ascites. Patients were treated with DIPS plus IVC stenting (group A, n=68) or DIPS alone (group B, n=21). A technical success rate of 100% was obtained in all 89 patients, and there were no early procedure-related adverse events or 30-day mortality. Mean portosystemic gradient decreased in both groups. Changes in aspartate and alanine aminotransferases and total bilirubin did not differ between the groups. Ascites disappeared in group A but was not obvious in group B until IVC stenting. During follow-up, recurrent bleeding and ascites and incidence of hepatic encephalopathy did not differ between the groups. The 1-, 3-, and 5-year survival rate was 98, 89.59, and 80%, respectively. Satisfactory clinical results were obtained for combined DIPS and IVC stenting for SOS associated with pyrrolizidine-alkaloid-related decompensated cirrhosis.

Effect of initial stent position on patency of transjugular intrahepatic portosystemic shunt.

AIM: To evaluate the effect of initial stent position on transjugular intrahepatic portosystemic shunt (TIPS). METHODS: We studied 425 patients from January 2004 to January 2015 with refractory ascites or variceal bleeding who required TIPS placement. Patients were randomly divided into group A (stent in hepatic vein, n = 57), group B (stent extended to junction of hepatic vein and inferior vena cava, n = 136), group C (stent in left branch of portal vein, n = 83) and group D (stent in main portal vein, n = 149). Primary unassisted patency was compared using Kaplan-Meier analysis, and incidence of recurrence of bleeding, ascites and hepatic encephalopathy (HE) were analyzed. RESULTS: The mean primary unassisted patency rate in group B tended to be higher than in group A at 3, 6 and 12 mo (P = 0.001, 0.000 and 0.005), and in group D it tended to be lower than in group C at 3, 6 and 12 mo (P = 0.012, 0.000 and 0.028). The median shunt primary patency time for group A was shorter than for group B (5.2 mo vs 9.1 mo, 95%CI: 4.3-5.6, P = 0.013, log-rank test), while for group C it was longer than for group D (8.3 mo vs 6.9 mo, 95%CI: 6.3-7.6, P = 0.025, log-rank test). Recurrence of bleeding and ascites in group A was higher than in group B at 3 mo (P = 0.014 and 0.020), 6 mo (P = 0.014 and 0.019) and 12 mo (P = 0.024 and 0.034. Recurrence in group D was higher than in group C at 3 mo (P = 0.035 and 0.035), 6 mo (P = 0.038 and 0.022) and 12 mo (P = 0.017 and 0.009). The incidence of HE was not significantly different among any of the groups (P = 0.965). CONCLUSION: The initial stent position can markedly affect stent patency, which potentially influences the risk of recurrent symptoms associated with shunt stenosis or occlusion.

Significance and clinical applications of ultrasound score in assessing the clinical severity of acute cholecystitis in the elderly.

OBJECTIVE: To investigate the feasibility and significance of the clinical application of ultrasound score in assessing the clinical severity of acute cholecystitis in the elderly. METHODS: Pre-surgery ultrasonography was performed on 72 elderly patients with acute cholecystitis who were scheduled for cholecystectomy to determine the score based on ultrasonic imaging features to reflect clinical severity. Prior to operation, the cases were classified as mild, moderate, and severe according to clinical manifestation. The significance of ultrasonography for the prediction of the severity of acute cholecystitis and its pre-surgery guidance were evaluated based on intraoperative findings and postoperative pathology. RESULT: In the aspect of clinical severity, of the 72 cases, 36 were mild, 21 were moderate, and 15 were severe. The cases that showed enlarged gallbladders, thickened gallbladder walls, double-layer images, gallbladder stones, incarcerated gall-stones, echoes in gallbladder fluid, peri-gallbladder effusions, or adherences were mostly moderate and severe cases. The difference in these cases with the mild cases exhibited statistical significance (P < 0.05). Of the 28 cases that scored ≤5, 26 (92.68 %) were mild cases. The 26 cases that scored between 6 and 9 mainly consisted of 15 moderate cases (57.7 %). The 18 cases that scored ≥10 mainly consisted of 13 severe cases (72.2 %). Significant differences were found in the cholecystostomy cases among the three groups (P < 0.05). CONCLUSION: Prior to cholecystectomy, ultrasound score could accurately determine the severity of acute cholecystitis in the elderly and may be used as a reference for surgical intervention timing and mode selection to guide clinical therapy.

Application of vertebral artery ultrasonography in enlistment-age male student pilots.

The aim of this study was to investigate the vertebral artery (VA) morphology of enlistment-age male student pilots with ultrasound to provide a basis for early diagnosis of potentially asymptomatic cervical vertigo. Ultrasound results of the origin position, diameter and hemodynamics of the VA in 935 cases of student pilots with a mean age of 18.0 y were analyzed. The inner diameters of both sides of the VA differ: the left is larger than the right statistically (p < 0.001). Moreover, the peak systolic velocity of the left VA is significantly greater than that of the right (p < 0.001). Congenital VA anomalies in age-appropriate male student pilots included inner diameter variation, course variation and origin position variation. The incidence of course variation or origin position proportion was low (3.46%, 32/925), and origin position variation was often accompanied by inner diameter variation or course variation. This study confirms that there are a variety of congenital abnormalities in the vertebral arteries of enlistment-age male student pilots, and a VA diameter <2.5 mm may be a reasonable criterion for diagnosis of VA hypoplasia.

Investigation of membranous ventricular septal defect complicated with tricuspid regurgitation in ventricular septal defect occlusion.

This study aimed to explore the mechanism of membranous ventricular septal defect complicated with tricuspid regurgitation and the significance of ventricular septal defect occlusion by echocardiography. A total of 43 patients with membranous ventricular septal defect complicated with tricuspid regurgitation were observed by echocardiography and the changes in length, area and volume of tricuspid regurgitation prior to and following ventricular septal defect occlusion were measured. There were four different mechanisms of membranous ventricular septal defect complicated with tricuspid regurgitation. The various indices of tricuspid regurgitation volume were significantly reduced following occlusion. Ventricular septal defect occlusion significantly reduces tricuspid regurgitation volume complicated with membranous ventricular septal defect and echocardiography is an ideal method to detect these changes.

Laparoscopic ultrasound enhances diagnosis and localization of insulinoma in pancreatic head and neck for laparoscopic surgery with satisfactory postsurgical outcomes.

This study explored the value of laparoscopic ultrasonography (LUS) for tumor localization in laparoscopic pancreatic surgery of insulinomas, especially for tumors located at anatomically unfavorable positions. Twenty-eight patients with insulinomas were enrolled in this study between July 2007 and March 2009. Various image examinations were performed preoperatively. An iU22 ultrasound system equipped with a 5.0-9.0 MHz transducer was used for LUS. The tumor localization and postsurgical outcomes were evaluated. Intraoperative LUS precisely localized 33 insulinomas in 26 of 28 patients, whereas the preoperative imaging studies detected 27 of 33 (82%) tumors. No definite tumor in the pancreas and extra-pancreatic organs was identified in two patients by both preoperative and intraoperative imaging examinations. Of 33 tumors, 32 (97%) were localized in the pancreas (14 in the head and neck, 18 in the body and tail), whereas one (3%) was found in the duodenal ligament. Successful laparoscopic resection of insulinoma was performed in 21 of 26 patients, including resection of 11 tumors located in the head and neck of the pancreas. Five patients required conversion to open surgery. All insulinomas were benign with a mean size 13.8 mm. Four patients had pancreatic-related complications that spontaneously healed within 3 weeks after surgery. The median hospital stay was 8.5 days. Our study demonstrates that laparoscopic pancreatic resection under the guidance of advanced LUS is not only feasible and safe for tumors located at the body and tail but also for tumors located at the head and neck of the pancreas.

Assessment of contrast-enhanced ultrasonography in diagnosis and preoperative localization of insulinoma.

OBJECTIVE: This study was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the diagnosis and preoperative localization of insulinoma and explore the enhancement patterns of the tumors. METHODS: Unenhanced and contrast-enhanced ultrasonographic examinations of 31 patients who underwent resection of insulinomas were retrospectively reviewed. The diagnosis sensitivity and localization specificity of CEUS for insulinomas were determined. Results of unenhanced ultrasonography and CEUS were compared by Chi-square test. RESULTS: Unenhanced ultrasonography could display 9 of 37 (24.3%) surgically verified insulinomas in 31 patients, while the diagnosis sensitivity and localization specificity of preoperative CEUS was 33 (89.2%) and 32 (86.5%) of the 37 tumors, respectively. In contrast to the unenhanced ultrasonography, the improvement of CEUS in the diagnosis and preoperative localization of insulinomas was significant (p<0.0001). The enhancement pattern of insulinoma on CEUS was fast wash-in and slow wash-out. All the tumors were homogeneous hypervascularity in the earlier arterial phase, while the tumors still displayed hyperenhancing pattern in the late phase. CONCLUSION: Our study demonstrates the great potential of CEUS in the diagnosis and preoperative localization of insulinomas. Since CEUS is a convenient, inexpensive, effective and non-invasive modality, the study supports the use of CEUS as a primary tool in the evaluation of patients with insulinomas.