Quantitative Dual-Energy CT Image Guidance for Thermochemical Ablation: In Vivo Results in the Rabbit VX2 Model.

PURPOSE: To evaluate the feasibility of using dual-energy computed tomography (CT) and theranostic cesium hydroxide (CsOH) for image guidance of thermochemical ablation (TCA) in a rabbit VX2 tumor model. MATERIALS AND METHODS: In vivo experiments were performed on New Zealand white rabbits, where VX2 tumor fragments (0.3 mL) were inoculated into the right and left flanks (n = 16 rabbits, 32 tumors). Catheters were placed in the approximate center of 1- to 2-cm diameter tumors under ultrasound guidance. TCA was delivered in 1 of 3 treatment groups: untreated control, 5-M TCA, or 10-M TCA. The TCA base reagent was doped with 250-mM CsOH. Dual-energy CT was performed before and after TCA. Cesium (CS)-specific images were postprocessed on the basis of previous phantom calibrations to determine Cs concentration. Line profiles were drawn through the ablation center. Twenty-four hours after TCA, subjects were euthanized, and the resulting damage was evaluated with histopathology. RESULTS: Cs was detected in 100% of treated tumors (n = 21). Line profiles indicated highest concentrations at the injection site and decreased concentrations at the tumor margins, with no Cs detected beyond the ablation zone. The maximum detected Cs concentration ranged from 14.39 to 137.33 mM. A dose-dependent trend in tissue necrosis was demonstrated between the 10-M TCA and 5-M TCA treatment groups (P = .0005) and untreated controls (P = .0089). CONCLUSIONS: Dual-energy CT provided image guidance for delivery, localization, and quantification of TCA in the rabbit VX2 model.

Prehabilitation for Hepatopancreatobiliary Surgical Patients: Interim Analysis Demonstrates a Protective Effect From Neoadjuvant Chemotherapy and Improvement in the Frailty Phenotype.

BACKGROUND: Prehabilitation encompasses multidisciplinary interventions to improve health and lessen incidence of surgical deterioration by reducing physiologic stress and functional decline. This study presents an interim analysis to demonstrate prehabilitation for hepatopancreatobiliary (HPB) surgical patients. METHODS: In 2018, a structured prehabilitation pilot program was implemented. Eligibility required HPB malignancy, neoadjuvant chemotherapy, and residence within hour drive. Patients were enrolled into the 4-month program. The fitness component was composed of timed up and go test and grip strength with exercise recommendations. Nutrition involved evaluation of sarcopenic obesity, glucose management, and smoking and alcohol counseling. Psychological services included psychosocial assessments and advanced care planning, with social work referrals. Component were evaluated monthly by a physician using laboratory results, nutritional data and questionnaires, psychological assessments, and validated fitness tests. Nurse navigators spoke with patients weekly to monitor compliance. RESULTS: At 12 months, nineteen patients were enrolled. Ten completed prehabilitation, neoadjuvant chemotherapy and underwent their surgical procedure. There were no differences found after prehabilitation in functional status, physical performance, psychosocial assessments, or nutrition. Frailty, as assessed by Fried frailty criteria, improved significantly after prehabilitation (P < .0001). Symptom severity and laboratory values did not change. Length of stay was 6.5 days and all patients were discharged to home. There was 1 readmission for transient ischemic attack and 90-day mortality rate was 0%. DISCUSSION: Prehabilitation to improve recovery is a promising concept encompassing a wide array of multidisciplinary assessments and interventions. It may demonstrate a protective effect on physiologic decline from chemotherapy and may reverse frailty phenotypes.

Drag reducing polymers attenuate adverse effects of ischemia-reperfusion upon resection of liver metastases modeled by MC38 mouse colon adenocarcinomama.

BACKGROUND: The resection of metastases within healthy parenchyma improves significantly the long-term outcome in metastatic colorectal cancer. Until now, the resection technique involves Pringle maneuver, which allows reducing blood loss during transsection of liver parenchyma. However, the classical Pringle maneuver has restrictions due to ischemia/reperfusion (I/R) effect, in particular increasing risk of tumor recurrence after liver surgery. AIM: To study the pathological impact of surgical intervention and I/R effect on healthy liver tissue in the experimental setting by evaluating the markers of redox-homeostasis and oxidatively induced mutage-nesis, and also to assess the current possibilities of their correction by application of drag-reducing polymers (DRPs). MATERIALS AND METHODS: MC38 mouse colon adenocarcinoma cells were transplanted intrahepatically to C57Bl/6 mice. The influence of warm ischemia on metastatic potential of MC38 cells, the speed of superoxide radicals (SR) generation and 8-hydroxydeoxyguanosine content were studied. RESULTS: In case of modeled liver metastases, the surgery initiates an increase in the rate of SR generation into the remaining liver tissue and, consequently, provokes its ischemic injury. The application of DRPs protects liver tissue under I/R conditions. CONCLUSIONS: The warm I/R can promotes metastatic lesions in the healthy part of the organ with underlying increase in the rate of SR generation and oxidatively induced damage of guanine in DNA. The hemorheological effects of DRPs ensure increase of microcirculatory perfusion and oxygenation of liver tissues with the reduction of the rate of SR generation and decrease of 8-hydroxydeoxyguanosine as a marker of oxidatively induced mutations in DNA of hepatocytes. The intraperitoneal administration of nanomolar doses of DRPs prevents the activation of the growth of dormant metastatic MC38 cells in the liver. Further experimental and clinical study of these substances will allow reducing the risks of activation of uncontrolled tumor growth in the liver due to the pathological effect of post-operative I/R.

Thermal Ablation Induces Transitory Metastatic Growth by Means of the STAT3/c-Met Molecular Pathway in an Intrahepatic Colorectal Cancer Mouse Model.

Background Systemic protumorigenic effects have been noted after radiofrequency ablation (RFA) of normal liver and have been linked to an interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-Met)/vascular endothelial growth factor (VEGF) cytokinetic pathway. Purpose To elucidate kinetics of RFA protumorigenic effects on intrahepatic metastatic implantation and growth and determine potential molecular targets for pharmacologic suppression of these effects. Materials and Methods An intrahepatic metastasis model was established by implanting CT26 and MC38 tumor cells into 216 7-8-week-old male Balb/C and C57BL6 mice, respectively, by means of splenic injection. Between June 2017 and March 2019, mice underwent tumor injection, followed 24 hours later by either standardized RFA (70°C ± 1, 5 minutes, 1-cm tip) or a sham procedure (needle placement without heating) (12 animals per arm, n = 48). Next, RFA or sham procedures were performed, followed by splenic tumor cell injection at 1 day, 3 days, or 7 days later (six animals per arm, n = 72). Finally, PHA-665752 and S3I-201 were used to block c-Met or STAT3, respectively, prior to either RFA or sham treatment (six animals per arm, n = 96). Livers were harvested at 14 days for CT26 and 21days for MC38 for tumor quantification. Ki-67 and CD34 immunohistochemistry measured proliferative indexes and microvascular density, respectively. Data were compared with analysis of variance and the two-tailed Student t test. Results RFA performed after tumor cell injection induced increased metastatic tumor number (103 ± 45 vs 52 ± 44 [CT26], P = .009 and 87 ± 51 vs 39 ± 20 [MC38], P = .007), cellular proliferation (P < .001 for both), and intratumoral neovascularization (P < .001 for both), compared with the sham procedure. Tumor cell injection performed 1 day and 3 days after RFA also increased these indexes (P < .05), while no difference was demonstrated for cell injection 7 days after RFA (P > .05). Adjuvant c-Met or STAT3 inhibition reduced intrahepatic metastatic parameters after RFA to baseline (P < .03), equivalent to the sham group (P > .05). Conclusion Radiofrequency ablation of normal liver promotes intrahepatic metastatic implantation and increased growth over a short-lived (1-3 days) temporal window in animal models. This phenomenon can be potentially neutralized with specific inhibition of pathways including hepatocyte growth factor/tyrosine-protein kinase Met and signal transducer and activator of transcription 3. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Nikolic in this issue.

Effect of laparoscopic liver resection versus the open technique on hepatocyte regenerating activity in the rat.

BACKGROUND: Laparoscopic liver resection offers a safe and feasible option primarily for the excision of hepatic neoplasms. Timely recovery of liver volume is a key factor for improving prognosis and post-operative mortality of patients undergone liver resection. The aim of the present study was to compare liver regeneration after laparoscopic over open partial hepatectomy. METHODS: Wistar rats were subjected to laparoscopic 70% hepatectomy (group LAP-HEP), open 70% hepatectomy (group HEP), sham operation (group Sham) or no intervention (group Control). At various timepoints following operation (1 h-2 weeks), the liver was excised to assess relative liver weight, thiobarbituric acid reactive substances (TBARS) levels, mitotic activity, tissue expression of Nuclear Factor-κB (NFκB), Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1) and the histopathologic profile. RESULTS: No differences were seen in relative liver weight between hepatectomy groups. Mitotic index was increased in all operative study groups, being higher in group LAP-HEP than in group HEP. TBARS levels were higher in group LAP-HEP compared to group HEP. NFκB and VCAM-1 tissue expression scores were increased in all operative study groups with VCAM-1 being higher in group HEP, while ICAM-1 was overexpressed only in hepatectomy groups. Mild histopathologic lesions were noted in hepatectomy groups with the histopathologic score being higher in group HEP (24 h). CONCLUSIONS: Laparoscopic liver resection enhanced hepatocyte mitotic activity which was accompanied by mild oxidative stress and a less pronounced local inflammatory response and tissue injury to that of the open technique.

Hepatic Microwave Ablation-Induced Tumor Destruction and Animal End Point Survival Can Be Improved by Suppression of Heat Shock Protein 90.

OBJECTIVES: To investigate the effect of heat shock protein 90 (HSP90) modulation on tumor necrosis, apoptosis, tumor growth delay, and end point survival by combining microwave ablation (MWA) with an HSP90 inhibitor in a nude mouse model. METHODS: This study was approved by the Ethics Committee. Forty mice with HepG2 subcutaneous xenograft tumors (10 ± 1 mm) were randomized into 4 groups: (1) no treatment, (2) MWA only, (3) the HSP90 inhibitor ganetespib only, and (4) ganetespib combined with MWA. Tumors were harvested 24 hours after treatment, and gross coagulation diameters were measured. The effect of ganetespib on HSP90 and caspase 3 expression in the periablational rim was assessed. Another 40 mice with the same tumors and groupings were observed after treatment. Tumor growth curve and Kaplan-Meier survival analyses were performed with a tumor diameter of 2.2 cm and 40 days of survival as the defined survival end points. RESULTS: Combination treatment significantly increased the coagulation size compared to tumors treated with MWA or ganetespib alone (P < 0.05). The combination of MWA and ganetespib decreased HSP90 expression and increased cleaved caspase 3 expression 24 hours after treatment. Compared with MWA or ganetespib only, combination treatment could lengthen the end point survival and reduce the tumor growth rate. CONCLUSIONS: Modulation of HSP production can improve MWA-induced tumor apoptosis and destruction, reduce residual tumor growth rates, and prolong end point survival.

Potential of Ablation Therapy during Hepatocellular Carcinoma.

BACKGROUND: This study explored the potential of ablation therapy on membrane fluidity changes in diethylnitrosamine (DEN) induced hepatic cancer. METHODS: Male Wistar rats were segregated into four groups viz., normal control, DEN treated, ablation therapy treated, and DEN ablation therapy treated. We assessed the viscosities as well as fluidity parameters in isolated brush border membranes using the membrane extrinsic fluorophore pyrene. RESULTS: DEN treatment successfully induced hepatic cancer in the livers of rats and ablation therapy worked well in terms of therapy. DEN treatment resulted in a significant rise in lipid peroxidation (LPO) and significant decrease in the, reduced glutathione levels (GSH). A significant decrease was also noticed in the activities of glutathione reductase (GR), glutathione transferase (GST), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) following DEN treatment. On the other hand, ablation therapy treatment to DEN-treated rats resulted in a significant decrease in the LPO levels but caused a significant rise in the levels of GSH. Moreover, the activities of GR, GST, SOD, CAT, and GPx showed significant improvement after ablation therapy treatment. The results further demonstrated a marked decrease in membrane microviscosity following DEN treatment. On the other hand, a significant increase was noticed in both excimer/monomer ratio and fluidity parameter in DEN-treated rats. However, membrane microviscosity and the fluidity alterations were significantly restored back to near normal with ablation therapy treatment. CONCLUSIONS: The study, therefore, concluded that ablation therapy holds good therapeutic potential against DEN-induced hepatic cancer.

Dual-Energy CT-Derived Volumetric Iodine Concentration for the Assessment of Therapeutic Response after Microwave Ablation in a Rabbit Model with Intrahepatic VX2 Tumor.

PURPOSE: To evaluate whether changes in volumetric iodine concentration (VIC) could serve as a suitable predictor of therapeutic response to microwave (MW) ablation in a rabbit intrahepatic VX2 tumor model. MATERIALS AND METHODS: Sixteen intrahepatic VX2 tumors were transplanted in 8 New Zealand White rabbits treated with MW ablation. Contrast-enhanced dual-energy CT scans were obtained at baseline and follow-up. Therapeutic response assessment by modified Response Evaluation Criteria In Solid Tumors (mRECIST), Choi criteria, and VIC changes was performed. An intraclass correlation coefficient (ICC) was used to characterize consistency of assessment results among the criteria used. Technical success was evaluated with explant pathologic findings as a reference. Correlations between technical success and variations in diameter, CT density, and VIC were analyzed. RESULTS: Disease control was observed in 4, 8, and 10 of the 16 tumors per mRECIST, Choi criteria, and VIC changes, respectively. VIC exhibited strong consistency (ICC = 0.807, P < .0001) with Choi criteria. According to explant pathology, technical success was achieved in 10 of the 16 tumors. There was a moderate correlation between VIC changes and technical success (r = 0.532, P = .034), and no correlation was found between technical success and variations in diameter or CT density. CONCLUSIONS: Compared with mRECIST and Choi criteria, dual-energy CT-derived VIC allowed for better prediction of therapeutic response after MW ablation and could provide a potential imaging biomarker of tumor response to MW ablation in patients with hepatocellular carcinoma.

Analysis of laparoscopic laser liver resection in standardized porcine model.

BACKGROUND: Hepatocellular carcinoma is a highly prevalent and lethal primary neoplasia of the liver and metastases of other malignancies affect most frequently the liver. Minimally invasive surgical approach for liver resections is advancing. Dissection of liver parenchyma by laparoscopic technique remains challenging and new technologies are in need. Therefore, we asked whether it is feasible to dissect liver tissue comparably in terms of speed and hemostasis with a non-contact 1.9-µm cw-laser device and whether there are differences in the postoperative healing process compared to a gold standard device (ultrasound aspirator) in an experimental model. METHODS: Laparoscopic laser and ultrasound aspirator standardized partial liver resections were performed in seven pigs. Resection time, hemostasis time, and blood loss were evaluated. After at least 10 days, representative specimen of the resection areas was collected via re-laparoscopy and biopsy and side effects like hematoma, abscess, or bilioma were noted. Histologically, coagulation necrosis margin, granulation tissue zone, tissue fibrosis, and giant cell count were analyzed. RESULTS: Laparoscopic laser liver resection was three times faster compared to the laparoscopic ultrasound aspirator. Blood loss was equal in both groups. No side effects like hematoma or bilioma occurred. Histologically, specimen showed the same expansion of coagulation necrosis zone and granulation tissue. Fibrotic scar could be determined in three cases in both groups, respectively. However, giant cell count was significant higher in the laser resection group. CONCLUSIONS: The 1.9-µm cw-laser device enables a safe and fast liver resection in an experimental pig model compared to a gold standard (ultrasound aspirator) laparoscopic liver resection method. Wound healing is not interfered by laser liver resection.

Targeting STAT3 to Suppress Systemic Pro-Oncogenic Effects from Hepatic Radiofrequency Ablation.

Purpose To (a) identify key expressed genes in the periablational rim after radiofrequency ablation (RFA) and their role in driving the stimulation of distant tumor growth and (b) use adjuvant drug therapies to block key identified mediator(s) to suppress off-target tumorigenic effects of hepatic RFA. Materials and Methods This institutional animal care and use committee-approved study was performed in C57BL6 mice (n = 20) and F344 rats (n = 124). First, gene expression analysis was performed in mice after hepatic RFA or sham procedure; mice were sacrificed 24 hours to 7 days after treatment. Data were analyzed for differentially expressed genes (greater than twofold change) and their functional annotations. Next, animals were allocated to hepatic RFA or sham treatment with or without STAT3 (signal transducer and activator of transcription 3) inhibitor S3I-201 for periablational phosphorylated STAT3 immunohistochemistry analysis at 24 hours. Finally, animals with subcutaneous R3230 adenocarcinoma tumors were allocated to RFA or sham treatment with or without a STAT3 inhibitor (S3I-201 or micellar curcumin, eight arms). Outcomes included distant tumor growth, proliferation (Ki-67 percentage), and microvascular density. Results At 24 hours, 217 genes had altered expression (107 upregulated and 110 downregulated), decreasing to 55 genes (27 upregulated and 28 downregulated) and 18 genes (four upregulated, 14 downregulated) at 72 hours and 7 days, respectively. At 24 hours, STAT3 occurred in four of seven activated pathways associated with pro-oncogenic genes at network analysis. Immunohistochemistry analysis confirmed elevated periablational phosphorylated STAT3 24 hours after RFA, which was suppressed with S3I-201 (percentage of positive cells per field: 31.7% ± 3.4 vs 3.8% ± 1.7; P < .001). Combined RFA plus S3I-201 reduced systemic distant tumor growth at 7 days (end diameter: 11.8 mm ± 0.5 with RFA plus S3I-201, 19.8 mm ± 0.7 with RFA alone, and 15 mm ± 0.7 with sham procedure; P < .001). STAT3 inhibition with micellar curcumin also suppressed postablation stimulation of distant tumor growth, proliferation, and microvascular density (P < .01). Conclusion Gene expression analysis identified multiple pathways upregulated in the periablational rim after hepatic RFA, of which STAT3 was active in four of seven. Postablation STAT3 activation is linked to increased distant tumor stimulation and can be suppressed with adjuvant STAT3 inhibitors. © RSNA, 2017.

Microscopic assessment of the tissue-sparing potential of radiofrequency-assisted liver resection techniques in a porcine model.

BACKGROUND: The aim of the present study was to microscopically assess the tissue-sparing potential of contemporary radiofrequency-assisted liver resection (RF-LR) techniques. METHODS: Twenty-four pigs were subjected to either (1) partial hepatectomy (PH) using the sequential-coagulate-cut (SCC) technique (group SCC, n = 6) using a monopolar electrode, the technique using the bipolar electrode Habib-4X (group H, n = 6) or the "crush-clamp" technique (group CC, n = 6); or (2) sham operation (group Sham, n = 6). At 48 h post-operation, liver parenchyma proximal to the ablation rim was excised for histopathologic examination and immunohistochemical assessment of apoptosis (antibody M30) and inflammatory response (antibodies IL-6, TNFα and NFκB). RESULTS: Histopathologic index increased from the 1st to the 4th , the 1st to the 2nd or only the 1st cm from the inner margin of the ablation rim in group SCC, H or CC, respectively. The index was higher in group SCC compared to the other groups. Tissue expression of M30, IL-6, TNFα and NFκB increased in all PH groups, being higher and more expanded in group SCC, H, SCC and SCC, respectively. CONCLUSIONS: RF-LR techniques had variable microscopically assessed tissue-sparing effect. The Habib-4X proved to be less injurious compared to the SCC Belgrade technique regarding the severity and extent of tissue damage proximal to the ablation rim.

In vivo comparison of two navigation systems for abdominal percutaneous needle intervention.

PURPOSE: To compare the accuracy of a Kinect-Optical navigation system with an electromagnetic (EM) navigation system for percutaneous liver needle intervention. MATERIALS AND METHODS: Five beagles with nine artificial tumors were used for validation. The Veran IG4 EM navigation system and a custom-made Kinect-Optical navigation system were used. Needle insertions into each tumor were conducted with these two guidance methods. The target positioning error (TPE) and the time cost of the puncture procedures were evaluated. RESULTS: A total of 18 needle insertions were performed to evaluate the navigation accuracy of the two guidance approaches. The targeting error was 6.78 ± 3.22 mm and 8.72 ± 3.5 mm for the Kinect-Optical navigation system and the EM navigation system, respectively. There is no statistically significant difference in the TPE between the Kinect-Optical navigation system and the EM navigation system (p = 0.229). The processing time with the Kinect-Optical system (10 min) is similar to that of the Veran IG4 system (12 min). CONCLUSIONS: The accuracy of the Kinect-Optical navigation system is comparable to that of the EM navigation system.

Echo Decorrelation Imaging of Rabbit Liver and VX2 Tumor during In Vivo Ultrasound Ablation.

In open surgical procedures, image-ablate ultrasound arrays performed thermal ablation and imaging on rabbit liver lobes with implanted VX2 tumor. Treatments included unfocused (bulk ultrasound ablation, N = 10) and focused (high-intensity focused ultrasound ablation, N = 13) exposure conditions. Echo decorrelation and integrated backscatter images were formed from pulse-echo data recorded during rest periods after each therapy pulse. Echo decorrelation images were corrected for artifacts using decorrelation measured prior to ablation. Ablation prediction performance was assessed using receiver operating characteristic curves. Results revealed significantly increased echo decorrelation and integrated backscatter in both ablated liver and ablated tumor relative to unablated tissue, with larger differences observed in liver than in tumor. For receiver operating characteristic curves computed from all ablation exposures, both echo decorrelation and integrated backscatter predicted liver and tumor ablation with statistically significant success, and echo decorrelation was significantly better as a predictor of liver ablation. These results indicate echo decorrelation imaging is a successful predictor of local thermal ablation in both normal liver and tumor tissue, with potential for real-time therapy monitoring.

Irreversible Electroporation versus Radiofrequency Ablation: A Comparison of Local and Systemic Effects in a Small-Animal Model.

Purpose To compare both periablational and systemic effects of two mechanistically different types of ablation: thermal radiofrequency (RF) ablation and electroporative ablation with irreversible electroporation (IRE) in appropriately selected animal models. Materials and Methods Animal experiments were performed according to a protocol approved by the Animal Care Committee of Hebrew University. Female C57BL/6 mice (n = 165) were randomized to undergo either RF or IRE ablation of noncancerous normal liver. The inflammatory response, cell proliferation, interleukin 6 (IL-6) levels, and intactness of vessels in the liver were assessed at 6, 12, and 24 hours and at 3, 7, and 14 days after ablation (n = 122 for mechanistic experiments). Systemic effects were then assessed by comparing tumor formation in an Mdr2-knockout (KO) mouse model (n = 15) and tumor growth in a remote BNL 1ME hepatoma xenograft tumor (n = 28). Results were averaged and evaluated by using two-tailed t tests. Results Although RF ablation was associated with a well-defined periablational inflammatory rim, for IRE, the infiltrate penetrated the ablation zone, largely along persistently patent vessels. Peak IL-6 levels (6 hours after ablation) were 10 and three times higher than at baseline for IRE and RF, respectively (P < .03). Mdr2-KO mice that were treated with IRE ablation had more tumors that were 3 mm or larger than mice treated with RF ablation or sham operation (mean, 3.6 ± 1.3 [standard deviation] vs 2.4 ± 1.1 and 2.2 ± 0.8, respectively; P < .05 for IRE vs both RF ablation and sham operation). For BNL 1ME tumors, both RF and IRE liver ablation reduced tumor growth, with a greater effect noted for IRE (1329 mm(3) ± 586 and 819 mm(3) ± 327 vs 2241 mm(3) ± 548 for sham operation; P < .05) that was accompanied by more infiltrating lymphocytes compared with sham operation (7.6 cells per frame ± 1.9 vs 11.2 ± 2.1 vs 0.3 ± 0.1; P < .05). Conclusion Persistent patency of vasculature within the coagulated zone from IRE increases the area and accumulation of infiltrative cells that is associated with a higher serum IL-6 level than RF ablation. These local changes of IRE induce more robust systemic effects, including both tumorigenic and immunogenic effects. (©) RSNA, 2016 Online supplemental material is available for this article.

Stress Test of Contrast-Enhanced US with Phenylephrine in a Rabbit VX2 Liver Tumor Model: Differentiating Benign Periablational Enhancement from Residual Tumor after Radiofrequency Ablation.

PURPOSE: To differentiate benign periablational enhancement (BPE) from residual tumor after radiofrequency (RF) ablation by using a stress contrast-enhanced ultrasonography (US) test with phenylephrine in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumors were implanted in the livers of 40 rabbits for two experiments. In experiment one, liver tumors from 32 animals were completely ablated. On days 2, 7, 14, and 21 after RF ablation, eight animals were randomly chosen for contrast-enhanced US before and after phenylephrine administration, and the microvessel density (MVD) of BPE at these four time points was assessed. In experiment two, liver tumors from eight animals were partly ablated, and each animal underwent contrast-enhanced US before and after phenylephrine administration on day 7 after RF ablation. Perfusion parameters were observed, including maximum intensity (IMAX), rise time (ie, time between 10% and 90% of IMAX), time to peak, mean transit time, and area under the curve (AUC), along with the profile of time-intensity curves (TICs) in BPE and residual tumor in response to phenylephrine. RESULTS: Among the four time points after ablation, the IMAX and AUC before phenylephrine administration and the MVD of BPE were greatest on day 7 (P < .05). The profile of TICs and the corresponding perfusion parameters in residual tumor did not change significantly in response to phenylephrine. However, those from BPE changed significantly (P < .05). CONCLUSIONS: Contrast-enhanced US with phenylephrine stress may be helpful in differentiating BPE from residual tumor after RF ablation in hepatocellular carcinoma.

Intraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided Surgery.

Difficulties in the highly sensitive detection of tumour microfoci represent a critical obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons' subjective experience are limited by their inability to effectively detect tumour lesions measuring less than 2 mm; however, intraoperative fluorescence molecular imaging may overcome this limitation. Here, we synthesised an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumour-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumour specificity enabled the identification of residual microtumours and satellite lesions measuring less than 1 mm in living mice. Histological analysis validated the sensitivity and accuracy of this approach. We believe this technique utilising a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.

Research of electrosurgical unit with novel antiadhesion composite thin film for tumor ablation: Microstructural characteristics, thermal conduction properties, and biological behaviors.

The objective of this study was to use surface functionalization to evaluate the antiadhesion property and thermal injury effects on the liver when using a novel electrosurgical unit with nanostructured-doped diamond-like carbon (DLC-Cu) thin films for tumor ablations. The physical and chemical properties of DLC-Cu thin films were characterized by contact angle goniometer, scanning electron microscope, and transmission electron microscope. Three-dimensional (3D) hepatic models were reconstructed using magnetic resonance imaging to simulate a clinical electrosurgical operation. The results indicated a significant increase of the contact angle on the nanostructured DLC-Cu thin films, and the antiadhesion properties were also observed in an animal model. Furthermore, the surgical temperature in the DLC-Cu electrosurgical unit was found to be significantly lower than the untreated unit when analyzed using 3D models and thermal images. In addition, DLC-Cu electrodes caused a relatively small injury area and lateral thermal effect. The results indicated that the nanostructured DLC-Cu thin film coating reduced excessive thermal injury and tissue adherence effect in the liver.

Improved disease-free survival and overall survival after fluorescence-guided surgery of liver metastasis in an orthotopic nude mouse model.

BACKGROUND: In the present study, we sought to determine if fluorescence-guided surgery (FGS) would improve survival compared to standard bright light surgery (BLS) in an experimental colorectal liver metastasis nude mouse model. METHODS: Orthotopic nude-mouse models of human HT-29-GFP colon cancer liver metastasis were established in the left lobe of the liver of mice. Fourteen mice with a single liver metastasis were randomized into FGS or BLS groups of seven each. FGS of liver metastasis was performed using a hand-held portable fluorescence imaging system (Dino-Lite) to visualize the GFP fluorescence of the metastasis. The BLS- and FGS-treated mice were followed by weekly fluorescence imaging in order to detect recurrence. RESULTS: The bright fluorescence of GFP provided sufficient illumination to accurately distinguish the margins of the metastasis within the liver. Recurrence occurred in multiple sites including the liver, lung, and other organs in the BLS-treated mice but was significantly reduced in FGS-treated mice. The FGS-treated mice had significantly prolonged disease-free survival (P = 0.001) and overall survival (P = 0.027) compared to BLS-treated mice. CONCLUSION: The results of the present report demonstrate the feasibility and efficacy of FGS for liver metastasis and suggest its important clinical potential.

Percutaneous ultrasound guided implantation of VX2 for creation of a rabbit hepatic tumor model.

Creation of a VX2 tumor model has traditionally required a laparotomy and surgical implantation of tumor fragments. Open surgical procedures are invasive and require long procedure times and recovery that can result in post-operative morbidity and mortality. The purpose of this study is to report the results of a percutaneous ultrasound guided method for creation of a VX2 model in rabbit livers. A total of 27 New Zealand white rabbits underwent a percutaneous ultrasound guided approach, where a VX2 tumor fragment was implanted in the liver. Magnetic resonance imaging was used to assess for tumor growth and necropsy was performed to determine rates of tract seeding and metastatic disease. Ultrasound guided tumor implantation was successful in all 27 rabbits. One rabbit died 2 days following the implantation procedure. Two rabbits had no tumors seen on follow-up imaging. Therefore, tumor development was seen in 24/26 (92%) rabbits. During the follow-up period, tract seeding was seen in 8% of rabbits and 38% had extra-hepatic metastatic disease. Therefore, percutaneous ultrasound guided tumor implantation safely provides reliable tumor growth for establishing hepatic VX2 tumors in a rabbit model with decreased rates of tract seeding, compared to previously reported methods.

Inflammation and cancer: inhibiting the progression of residual hepatic VX2 carcinoma by anti-inflammatory drug after incomplete radiofrequency ablation.

BACKGROUND: Accelerated progression of residual hepatocellular carcinoma (HCC) after incomplete radiofrequency ablation (RFA) has been reported more frequently. Recent data have redefined the concept of inflammation as a critical component of tumor progression. However, there has been little understanding regarding the relationship between progression of residual HCC and the inflammation induced by thermal destruction of the tumor after RFA. The present study was designed to determine whether inflammation facilitates rapid progression of residual hepatic VX2 carcinoma and to clarify the possible underlying mechanisms. METHODS: Forty-eight rabbits were each implanted with two VX2 hepatic tumors via supraumbilical median laparotomy. One of the tumors in two different lobes was ablated by RFA. All the rabbits were then randomly divided into four groups (12 rabbits in each group) receiving anti-inflammatory treatment with different doses of aspirin: control group, AS-L group (aspirin, 5 mg/kg/d), AS-M group (aspirin, 20 mg/kg/d), and AS-H group (aspirin, 100 mg/kg/d). The levels of serum interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), and tumor necrosis factor-α (TNF-α) were detected to evaluate the effect of the anti-inflammation. Tumor growth, lung and kidney metastasis, and survival were assessed. The expression of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 9 (MMP-9), vascular endothelial growth factor (VEGF), and cysteinyl aspartate specific proteinase 3 (caspase-3) in residual tumor was examined by immunohistochemistry and Western-blotting. RESULTS: The levels of serum IL-6, hs-CRP, and TNF-α in the AS-H group decreased significantly in comparison with those of the control group (P<0.05). The focal tumor volume and lung and kidney metastases of rabbits in the AS-H group were less significant compared with those of the control group (P<0.05). The expression of PCNA, MMP-9, and VEGF in the AS-H group decreased significantly compared with the control group (P<0.05). Finally, the survival time of the AS-H group was longer than that of the control group (P<0.05). CONCLUSIONS: Inflammation induced by thermal destruction of the tumor following RFA could be an important cause of rapid progression of residual hepatic VX2 carcinoma. The anti-inflammation effect of aspirin can inhibit proliferation, invasion, and metastasis of residual tumor cells, and aspirin may be a good candidate drug as an adjuvant therapy with RFA for treating HCC.