18F-FDG PET Biomarkers Help Detect Early Metabolic Response to Irreversible Electroporation and Predict Therapeutic Outcomes in a Rat Liver Tumor Model.

Purpose To test the hypothesis that biomarkers of fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used for the early detection of therapeutic response to irreversible electroporation (IRE) of liver tumor in a rodent liver tumor model. Materials and Methods The institutional animal care and use committee approved this study. Rats were inoculated with McA-RH7777 liver tumor cells in the left median and left lateral lobes. Tumors were allowed to grow for 7 days to reach a size typically at least 5 mm in longest diameter, as verified with magnetic resonance (MR) imaging. IRE electrodes were inserted, and eight 100-µsec, 2000-V pulses were applied to ablate the tumor tissue in the left median lobe. Tumor in the left lateral lobe served as a control in each animal. PET/computed tomography (CT) and MR imaging measurements were performed at baseline and 3 days after IRE for each animal. Additional MR imaging measurements were obtained 14 days after IRE. After 14-day follow-up MR imaging, rats were euthanized and tumors harvested for hematoxylin-eosin, CD34, and caspase-3 staining. Change in the maximum standardized uptake value (ΔSUVmax) was calculated 3 days after IRE. The maximum lesion diameter change (ΔDmax) was measured 14 days after IRE by using axial T2-weighted imaging. ΔSUVmax and ΔDmax were compared. The apoptosis index was calculated by using caspase-3-stained slices of apoptotic tumor cells. Pearson correlation coefficients were calculated to assess the relationship between ΔSUVmax at 3 days and ΔDmax (or apoptosis index) at 14 days after IRE treatment. Results ΔSUVmax, ΔDmax, and apoptosis index significantly differed between treated and untreated tumors (P < .001 for all). In treated tumors, there was a strong correlation between ΔSUVmax 3 days after IRE and ΔDmax 14 days after IRE (R = 0.66, P = .01) and between ΔSUVmax 3 days after IRE and apoptosis index 14 days after IRE (R = 0.57, P = .04). Conclusion 18F-FDG PET imaging biomarkers can be used for the early detection of therapeutic response to IRE treatment of liver tumors in a rodent model. © RSNA, 2017.

Diffusion MRI biomarkers predict the outcome of irreversible electroporation in a pancreatic tumor mouse model.

The purpose of this work is to explore the potential contribution of diffusion MRI to predict the effects of irreversible electroporation (IRE) in a pancreatic ductal adenocarcinoma (PDAC) mouse model. Thirteen mice were injected with Panc-02 PDAC cells in both flanks. One tumor was treated with IRE when it reached a diameter of about 5 mm. T2- and diffusion-weighted MRI sequences were acquired before IRE treatment and 1, 3 and 7 days later. The mice were euthanized 1 day (n = 6) or 2 weeks (n = 7) after treatment. The tumors were excised and stained with H&E, caspase-3, CD-3, F4/80. The volume and the mean and standard deviation of the apparent diffusion coefficient (ADC) were compared between treated and untreated lesions and correlated with histology-derived measures. At 1-day post-treatment, a dramatic ADC increase (+50.81%, P < 0.05) was found in ablated lesions, strongly correlated with apoptosis (τ = 0.90). At later time points the ADC returned to pre-treatment values, though histopathology showed a quite different scenario compared to the untreated controls. The ADC standard deviation measured within the treated tumors 1 day after IRE treatment had a strong negative correlation with the number of tumor cells found 14 days later (τ = 0.80). There was also a strong correlation between 1-day ADC and 14-day apoptosis in untreated tumors (τ = 0.95). In conclusion, diffusion MRI is sensitive to the short-term effects of IRE in PDAC tumors, and can help predict the long-term treatment outcome.

Gd-EOB-DTPA DCE-MRI biomarkers in a rabbit model of liver fibrosis.

The purpose of this study was to investigate the correlations between Gd-EOB-DTPA DCE-MRI biomarkers and histopathologic biomarkers of liver fibrosis progression in a rabbit model of liver fibrosis. Thirty-Six New Zealand white rabbits were randomly divided into control (n = 6) and liver fibrosis group (n = 30). Each rabbit in the liver fibrosis group received a weekly subcutaneous injection in the back comprising 50% carbon tetrachloride (CCl4) in oily solution. Control rabbits received subcutaneous injections with the same amount of normal saline solution instead. MR imaging was performed in control and fibrotic rabbits were conducted by MRI at week 0 (n = 36). The fibrotic rabbits were performed MR imaging on 6 weeks, 9 weeks, and 12 weeks after modeling of fibrosis. Before each MRI, peripheral blood was collected, and several biochemical testes are performed. The thirty-four rabbits completed this study. They were then divided into three subgroups according to fibrotic stage: no fibrosis (F0, n = 12), mild fibrosis (F1+F2, n = 14), and advanced fibrosis (F3+F4, n = 8). DCE-MRI measurements show increasing Ktrans and Ve while decreasing iACU90 with increasing fibrosis stage. The significant correlations were observed between mean Ktrans, Ve, iACU90 and percentage of the animal with mild liver fibrosis. For blood biomarkers, there were significant differences between F0 and F1+F2, and between F0 and F3+F4 in the serum levels of ALT (all P < 0.05), and TB (F0 vs. F1+F2, P = 0.004), while no differences were found between F1+F2 group and F3+F4 group (all P > 0.05). There were significant differences between F0 and F1+F2 (P = 0.02). Gd-EOB-DTPA DCE-MRI is a promising method for the noninvasive diagnosis and staging of liver fibrosis. Future studies to evaluate the effectiveness of these techniques in patients with liver fibrosis are warranted.

MRI-guided interventional natural killer cell delivery for liver tumor treatment.

While natural killer (NK) cell-based adoptive transfer immunotherapy (ATI) provides only modest clinical success in cancer patients. This study was hypothesized that MRI-guided transcatheter intra-hepatic arterial (IHA) infusion permits local delivery to liver tumors to improve outcomes during NK-based ATI in a rat model of hepatocellular carcinoma (HCC). Mouse NK cells were labeled with clinically applicable iron nanocomplexes. Twenty rat HCC models were assigned to three groups: transcatheter IHA saline infusion as the control group, transcatheter IHA NK infusion group, and intravenous (IV) NK infusion group. MRI studies were performed at baseline and at 24 h, 48 h, and 8 days postinfusion. There was a significant difference in tumor R2* values between baseline and 24 h following the selective transcatheter IHA NK delivery to the tumors (P = 0.039) when compared to IV NK infusion (P = 0.803). At 8 days postinfusion, there were significant differences in tumor volumes between the control, IV, and IHA NK infusion groups (control vs. IV, P = 0.196; control vs. IHA, P < 0.001; and IV vs. IHA, P = 0.001). Moreover, there was a strong correlation between tumor R2* value change (∆R2*) at 24 h postinfusion and tumor volume change (∆volume) at 8 days in IHA group (R2  = 0.704, P < 0.001). Clinically applicable labeled NK cells with 12-h labeling time can be tracked by MRI. Transcatheter IHA infusion improves NK cell homing efficacy and immunotherapeutic efficiency. The change in tumor R2* value 24 h postinfusion is an important early biomarker for prediction of longitudinal response.

Preclinical and clinical evaluation of the liver tumor irreversible electroporation by magnetic resonance imaging.

Irreversible electroporation (IRE) is a relatively new technique for tumor ablation. It has shown promising results in difficult cases where surgery is not recommended and delicate anatomic structures are present near or within the tumor. Currently, liver cancer is one of the most common targets for IRE treatment. Pre-operative and post-operative imaging has a key role in IRE procedures and research studies. Although ultrasound is usually the first choice, especially for intra-operative guidance, magnetic resonance imaging (MRI) plays an important role in the visualization and characterization of tumor before and after IRE in clinical and preclinical studies. However, the appearance of liver lesions after IRE with different MRI sequences has never been systematically investigated, and the most common practice is to limit the acquisition protocol to only contrast-enhanced T1-weighted images. In this work, the role of MRI in clinical and preclinical assessment of hepatic tumors treated with IRE is reviewed and discussed.

Irreversible electroporation in primary and metastatic hepatic malignancies: A review.

BACKGROUND: Liver cancer makes up a huge percentage of cancer mortality worldwide. Irreversible electroporation (IRE) is a relatively new minimally invasive nonthermal ablation technique for tumors that applies short pulses of high frequency electrical energy to irreversibly destabilize cell membrane to induce tumor cell apoptosis. METHODS: This review aims to investigate the studies regarding the use of IRE treatment in liver tumors and metastases to liver. We searched PubMed for all of IRE relevant English language articles published up to September 2016. They included clinical trials, experimental studies, observational studies, and reviews. This review manuscript is nothing with ethics issues and ethical approval is not provided. RESULTS: In recent years, increasingly more studies in both preclinical and clinical settings have been conducted to examine the safety and efficacy of this new technique, shedding light on the crucial advantages and disadvantages that IRE possesses. Unlike the current leading thermal ablation techniques, such as radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation, IRE requires shorter ablation time without damaging adjacent important vital structures. CONCLUSION: Although IRE has successfully claimed its valuable status in the field of hepatic cancer treatment both preclinical and clinical settings. In order to systemically test and establish its safety and efficacy for clinical applications, more studies still need to be conducted.

DWI as a Quantitative Biomarker in Predicting Chemotherapeutic Efficacy at Multitime Points on Gastric Cancer Lymph Nodes Metastases.

The purpose of the hypothesis testing is to determine that apparent diffusion coefficient (ADC) as an early biomarker can predict the metastatic lymph nodes' (LNs) response to neoadjuvant chemotherapy in advanced gastric cancer (GC) in early stage. From March 2011 to June 2015, 106 patients with advanced GC were enrolled in the study. Patients underwent conventional magnetic resonance imaging and functional diffusion weighted imaging before and 3 days, 7 days, 30 days, and 60 days following the standard chemotherapy. After surgery, among 3034 detected LNs, the positive group was divided into complete response (CR) group, partial response (PR) group, and stable disease (SD) group in accordance to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Mean ADCs, short/long diameters of LNs before chemotherapy between the whole positive and the negative LNs were compared by t test. Changes of mean ADCs in 3 groups were analyzed by 1-way ANOVA. The mean ADC of the whole positive LNs was (1.145 ±â€Š0.014) × 10⁻³ mm²/s, which was significantly lower than that of the whole negative LNs ([1.491 ±â€Š0.010] × 10⁻³ mm²/s; P < 0.05). The means of both short/long diameters in the whole positive LNs were significantly longer than those in the whole negative LNs (P < 0.05). In CR, PR, and SD groups, the mean ADC of metastatic LNs on the 3rd day, 7th day, 13th day, and 16th day following the chemotherapy were all higher than that of LNs before chemotherapy, respectively (all P < 0.05). In addition, significant difference was found between mean ADCs in any 2 time points (all P < 0.05), except between mean ADCs in the 3rd day and in the 7th day of the chemotherapy. In conclusion, ADC can be used as an early biomarker to predict the metastatic LNs' response to neoadjuvant chemotherapy in advanced GC in early stage.

Lymph node metastasis in patients with gastric cancer: a multi-modality, morphologic and functional imaging study.

The aim of the study was to investigate the value of computed tomography (CT), magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI) for diagnosing lymph nodes metastasis before treatment in gastric cancer. Eighty-two patients with proven gastric cancer underwent CT, morphological MRI (T2WI) and DWI examinations. Two radiologists independently assessed these images for the presence of lymph nodes involvement. Pathologic findings were considered as "gold standard". Independent samples t-test was used for the comparisons of short diameters and ADC values between the positive lymph nodes and the negative lymph nodes. Diagnostic accuracy of these three imaging modalities was evaluated by area under the receiver operating characteristics (ROC) curve (AUC). The ADC value of the positive lymph nodes was (1.15 ± 0.01) × 10-3 mm2/s, which was significantly lower than that of the negative lymph nodes (1.48 ± 0.01) × 10-3 mm2/s (t = 18.70, P < 0.0001). The short diameter of the positive lymph nodes (1.54 ± 0.38 cm) was significantly greater than that of the negative lymph nodes (0.95 ± 0.12 mm) (t = 19.03, P < 0.001). The AUC for all imaging modalities combined (0.893) was significantly larger than that for each imaging modality alone (P < 0.05), and the AUC of DWI (0.797) was significantly larger than (P < 0.05) that of morphological MRI (0.733). There was no statistically significant difference between the AUCs of CT and morphological MRI (P = 0.462). In conclusion, CT, MRI and DWI combined present significantly higher accuracy than each imaging modality alone in the detection of lymph nodes involvement.