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Pancreatic cancer remains one of the most lethal cancers, primarily due to its late diagnosis and limited treatment options. This review examines the challenges and potential of using immunotherapy to treat pancreatic cancer, highlighting the role of artificial intelligence (AI) as a promising tool to enhance early detection and monitor the effectiveness of these therapies. By synthesizing recent advancements and identifying gaps in the current research, this review aims to provide a comprehensive overview of how AI and immunotherapy can be integrated to develop more personalized and effective treatment strategies. The insights from this review may guide future research efforts and contribute to improving patient outcomes in pancreatic cancer management.

BackgroundHeterogeneity of hepatocellular carcinoma (HCC) presents significant challenges for therapeutic strategies and necessitates combinatorial treatment approaches to counteract suppressive behavior of tumor microenvironment and achieve improved outcomes. Here, we employed cytokines to induce memory-like behavior in natural killer (NK) cells, thereby enhancing their cytotoxicity against HCC. Additionally, we evaluated the potential benefits of combining sorafenib with this newly developed memory-like NK cell (pNK) immunochemotherapy in a preclinical model.MethodsHCC tumors were grown in SD rats using subcapsular implantation. Interleukin 12/18 cytokines were supplemented to NK cells to enhance cytotoxicity through memory activation. Tumors were diagnosed using MRI, and animals were randomly assigned to control, pNK immunotherapy, sorafenib chemotherapy, or combination therapy groups. NK cells were delivered locally via the gastrointestinal tract, while sorafenib was administered systemically. Therapeutic responses were monitored with weekly multi-parametric MRI scans over three weeks. Afterward, tumor tissues were harvested for histopathological analysis. Structural and functional changes in tumors were evaluated by analyzing MRI and histopathology data using ANOVA and pairwise T-test analyses.ResultsThe tumors were allowed to grow for six days post-cell implantation before treatment commenced. At baseline, tumor diameter averaged 5.27 mm without significant difference between groups (p = 0.16). Both sorafenib and combination therapy imposed greater burden on tumor dimensions compared to immunotherapy alone in the first week. By the second week of treatment, combination therapy had markedly expanded its therapeutic efficacy, resulting in the most significant tumor regression observed (6.05 ± 1.99 vs. 13.99 ± 8.01 mm). Histological analysis demonstrated significantly improved cell destruction in the tumor microenvironment associated with combination treatment (63.79%). Interestingly, we observed fewer viable tumor regions in the sorafenib group (38.9%) compared to the immunotherapy group (45.6%). Notably, there was a significantly higher presence of NK cells in the tumor microenvironment with combination therapy (34.79%) compared to other groups (ranging from 2.21 to 26.50%). Although the tumor sizes in the monotherapy groups were similar, histological analysis revealed a stronger response in pNK cell immunotherapy group compared to the sorafenib group.ConclusionsExperimental results indicated that combination therapy significantly enhanced treatment response, resulting in substantial tumor growth reduction in alignment with histological analysis.

Sorafenib, FDA-approved therapy for patients with advanced hepatocellular carcinoma (HCC), leads to limited improvement in overall survival. However, it may indirectly impact the expansion and activity of natural killer (NK) cells. While NK cell-based immunotherapies generally exhibit favorable safety profiles, their effectiveness in controlling solid tumor growth is constrained, primarily due to the absence of antigen specificity and suboptimal expansion and persistence within the tumor microenvironment. In this study, we postulated that enhancing NK cell functionality via cytokine activation could bolster their viability and cytotoxic capabilities, leading to an improved therapeutic response when combined with sorafenib. Memory-like (ML)-NK cells were generated through the supplementation of optimal concentrations of interleukin (IL)-12 and IL-18 cytokines. Following a single day of treatment, cytotoxicity against rat and human HCC cells was evaluated via flow cytometry analysis. A rat HCC model was developed in 30 animals via subcapsular implantation and assigned to control, NK, sorafenib, ML-NK, and combination groups. Sorafenib was administered orally, and NK cells were delivered via the intrahepatic artery. Tumor growth was measured one week after treatment evaluation. Therapeutic efficacy during in-vitro and in-vivo analysis was investigated through a one-way ANOVA test, followed by pairwise two-tailed Student t-tests, considering P < 0.05 statistically significant. The in-vitro experiment results demonstrated that sorafenib and conventional NK cell therapies induced more substantial cell death than the control group (P < 0.01). ML NK cells significantly improved cell death compared to conventional NK cell immunotherapy. Furthermore, sorafenib in combination with ML-NK cells significantly decreased the viability of HCC cells (P < 0.05) compared to sorafenib plus conventional NK cell combination therapy. In vivo experiments have shown that sorafenib and ML-NK cell immunotherapy reduced the growth rate of HCC tumors compared to conventional NK immunotherapy and control groups. Notably, a combination of sorafenib and ML-NK cell immunochemotherapy resulted in the most significant suppression of tumor growth when compared to other therapies. In conclusion, our experimental findings demonstrate that the concurrent administration of sorafenib and ML-NK immunotherapy enhances cytotoxicity against HCC by optimizing the therapeutic response through cytokine activation, resulting in a significant decrease in tumor growth.

BackgroundHepatocellular carcinoma (HCC) is a common liver malignancy with limited treatment options. Previous studies expressed the potential synergy of sorafenib and NK cell immunotherapy as a promising approach against HCC. MRI is commonly used to assess response of HCC to therapy. However, traditional MRI-based metrics for treatment efficacy are inadequate for capturing complex changes in the tumor microenvironment, especially with immunotherapy. In this study, we investigated potent MRI radiomics analysis to non-invasively assess early responses to combined sorafenib and NK cell therapy in a HCC rat model, aiming to predict multiple treatment outcomes and optimize HCC treatment evaluations.MethodsSprague Dawley (SD) rats underwent tumor implantation with the N1-S1 cell line. Tumor progression and treatment efficacy were assessed using MRI following NK cell immunotherapy and sorafenib administration. Radiomics features were extracted, processed, and selected from both T1w and T2w MRI images. The quantitative models were developed to predict treatment outcomes and their performances were evaluated with area under the receiver operating characteristic (AUROC) curve. Additionally, multivariable linear regression models were constructed to determine the correlation between MRI radiomics and histology, aiming for a noninvasive evaluation of tumor biomarkers. These models were evaluated using root-mean-squared-error (RMSE) and the Spearman correlation coefficient.ResultsA total of 743 radiomics features were extracted from T1w and T2w MRI data separately. Subsequently, a feature selection process was conducted to identify a subset of five features for modeling. For therapeutic prediction, four classification models were developed. Support vector machine (SVM) model, utilizing combined T1w + T2w MRI data, achieved 96% accuracy and an AUROC of 1.00 in differentiating the control and treatment groups. For multi-class treatment outcome prediction, Linear regression model attained 85% accuracy and an AUC of 0.93. Histological analysis showed that combination therapy of NK cell and sorafenib had the lowest tumor cell viability and the highest NK cell activity. Correlation analyses between MRI features and histological biomarkers indicated robust relationships (r = 0.94).ConclusionsOur study underscored the significant potential of texture-based MRI imaging features in the early assessment of multiple HCC treatment outcomes.

Sorafenib is an oral multikinase inhibitor approved by the US Food and Drug Administration for treatment of the patients with surgically unresectable hepatocellular carcinoma (HCC). Sorafenib mitigates angiogenesis by targeting vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes. Moreover, it suppresses cell proliferation via blockage of B-RAF and RAF1 of the mitogen-activated protein kinase pathway in tumor cells. Sorafenib has been the standard molecular targeted medication in the treatment of advanced-stage HCC patients ineligible for potentially curative interventional (radiofrequency or microwave ablation) or palliative trans-arterial chemoembolization (TACE) therapies for over a decade. However, it only increases overall survival by less than 3 months, and systemic exposure to sorafenib causes clinically significant toxicities (about 50% of patients). Given the high frequency and severity of these toxicities, sorafenib dose must be often reduced or discontinued altogether. In this review, we discussed the mechanism of sorafenib-associated adverse events and their management during HCC treatment.

Rationale and objectivesTo develop classification and regression models interpreting tumor characteristics obtained from structural (T1w and T2w) magnetic resonance imaging (MRI) data for early detection of dendritic cell (DC) vaccine treatment effects and prediction of long-term outcomes for LSL-KrasG12D; LSL-Trp53R172H; Pdx-1-Cre (KPC) transgenic mice model of pancreatic ductal adenocarcinoma.Materials and methodsEight mice were treated with DC vaccine for 3 weeks while eight KPC mice were used as untreated control subjects. The reproducibility of the computed 264 features was evaluated using the intraclass correlation coefficient. Key variables were determined using a three-step feature selection approach. Support vector machines classifiers were generated to differentiate treatment-related changes on tumor tissue following first- and third weeks of the DC vaccine therapy. The multivariable regression models were generated to predict overall survival (OS) and histological tumor markers of KPC mice using quantitative features.ResultsThe quantitative features computed from T1w MRI data have better reproducibility than T2w MRI features. The KPC mice in treatment and control groups were differentiated with a longitudinally increasing accuracy (first- and third weeks: 87.5% and 93.75%). The linear regression model generated with five features of T1w MRI data predicted OS with a root-mean-squared error (RMSE)

PurposeTo evaluate the effect of the anatomic size on 3D radiomic imaging features of the breast cancer hepatic metastases.Materials and methodsCT scans of 81 liver metastases from 54 patients with breast cancer were evaluated. Ten most common 3D radiomic features from the histogram and gray level co-occurrence matrix (GLCM) categories were calculated for the hepatic metastases (HM) and compared to normal liver (NL). The effect of size was evaluated by using linear mixed-effects regression models. The effect of size on different radiomic features was analyzed for both liver lesions and background liver.ResultsThree-dimensional radiomic features from GLCM demonstrate an important size dependence. The texture-feature size dependence was found to be different among feature categories and between the HM and NL, thus demonstrating a discriminatory power for the tissue type. Significant difference in the slope was found for GLCM homogeneity (NL slope = 0.004, slope difference 95% confidence interval [CI] 0.06-0.1, p

PurposeTo demonstrate a stronger correlation and agreement of yttrium-90 (90Y) positron emission tomography (PET)/computed tomography (CT) measurements with explant liver tumor dosing compared with the standard model (SM) for radioembolization.Materials and methodsHepatic VX2 tumors were implanted into New Zealand white rabbits, with growth confirmed by 7 T magnetic resonance imaging. Seventeen VX2 rabbits provided 33 analyzed tumors. Treatment volumes were calculated from manually drawn volumes of interest (VOI) with three-dimensional surface renderings. Radioembolization was performed with glass 90Y microspheres. PET/CT imaging was completed with scatter and attenuation correction. Three-dimensional ellipsoid VOI were drawn to encompass tumors on fused images. Tumors and livers were then explanted for inductively coupled plasma (ICP)-optical emission spectroscopy (OES) analysis of microsphere content. 90Y PET/CT and SM measurements were compared with reference standard ICP-OES measurements of tumor dosing with Pearson correlation and Bland-Altman analyses for agreement testing with and without adjustment for tumor necrosis.ResultsThe median infused activity was 33.3 MBq (range, 5.9-152.9). Tumor dose was significantly correlated with 90Y PET/CT measurements (r = 0.903, P < .001) and SM estimates (r = 0.607, P < .001). Bland-Altman analyses showed that the SM tended to underestimate the tumor dosing by a mean of -8.5 Gy (CI, -26.3-9.3), and the degree of underestimation increased to a mean of -18.3 Gy (CI, -38.5-1.9) after the adjustment for tumor necrosis.Conclusions90Y PET/CT estimates were strongly correlated and had better agreement with reference measurements of tumor dosing than SM estimates.

Pancreatic ductal adenocarcinoma (PDAC) is associated with highly immunosuppressive tumor microenvironment (TME) that can limit the efficacy of dendritic cell (DC) vaccine immunotherapy. Irreversible electroporation (IRE) is a local ablation approach. Herein, we test the hypothesis that IRE ablation can overcome TME immunosuppression to improve the efficacy of DC vaccination using KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) orthotopic mouse model of PDAC. The median survival for mice treated with the combined IRE and DC vaccination was 77 days compared with sham control (35 days), DC vaccination (49 days), and IRE (44 days) groups (P = .006). Thirty-six percent of the mice treated with combination IRE and DC vaccination were still survival at the end of the study period (90 days) without visible tumor. The changes of tumor apparent diffusion coefficient (ΔADC) were higher in mice treated with combination IRE and DC vaccination than that of other groups (all P

PurposePortal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague-Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy.MethodsTwenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide).ResultsEx vivo measurements confirmed 91-97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was - 5.0% (95% CI - 17.0-6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6-29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 μm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively.ConclusionY90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8-12 weeks.

BackgroundPreoperative detection of lymph node (LN) metastasis is critical for planning treatments in colon cancer (CC). The clinical diagnostic criteria based on the size of the LNs are not sensitive to determine metastasis using CT images. In this retrospective study, we investigated the potential value of CT texture features to diagnose LN metastasis using preoperative CT data and patient characteristics by developing quantitative prediction models.MethodsA total of 390 CC patients, undergone surgical resection, were enrolled in this monocentric study. 390 histologically validated LNs were collected from patients and randomly separated into training (312 patients, 155 metastatic and 157 normal LNs) and test cohorts (78 patients, 39 metastatic and 39 normal LNs). Six patient characteristics and 146 quantitative CT imaging features were analyzed and key variables were determined using either exhaustive search or least absolute shrinkage algorithm. Two kernel-based support vector machine classifiers (patient-characteristic model and radiomic-derived model), generated with 10-fold cross-validation, were compared with the clinical model that utilizes long-axis diameter for diagnosis of metastatic LN. The performance of the models was evaluated on the test cohort by computing accuracy, sensitivity, specificity, and area under the receiver operating curve (AUC).ResultsThe clinical model had an overall diagnostic accuracy of 64.87%; specifically, accuracy of 65.38% and 62.82%, sensitivity of 83.87% and 84.62%, and specificity of 47.13% and 41.03% for training and test cohorts, respectively. The patient-demographic model obtained accuracy of 67.31% and 73.08%, the sensitivity of 62.58% and 69.23%, and specificity of 71.97% and 76.23% for training and test cohorts, respectively. Besides, the radiomic-derived model resulted in an accuracy of 81.09% and 79.49%, sensitivity of 83.87% and 74.36%, and specificity of 78.34% and 84.62% for training and test cohorts, respectively. Furthermore, the diagnostic performance of the radiomic-derived model was significantly higher than clinical and patient-demographic models (p

BackgroundThere is a lack of well-established clinical tools for predicting dendritic cell (DC) vaccination response of pancreatic ductal adenocarcinoma (PDAC). DC vaccine treatment efficiency was demonstrated using histological analysis in pre-clinical studies; however, its usage was limited due to invasiveness. In this study, we aimed to investigate the potential of MRI texture features for detection of early immunotherapeutic response as well as overall survival (OS) of PDAC subjects following dendritic cell (DC) vaccine treatment in LSL-KrasG12D;LSL-Trp53R172H;Pdx-1-Cre (KPC) transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC).Materials and methodsKPC mice were treated with DC vaccines, and tumor growth was dynamically monitored. A total of a hundred and fifty-two image features of T2-weighted MRI images were analyzed using a kernel-based support vector machine model to detect treatment effects following the first and third weeks of the treatment. Moreover, univariate analysis was performed to describe the association between MRI texture and survival of KPC mice as well as histological tumor biomarkers.ResultsOS for mice in the treatment group was 54.8 ± 22.54 days while the control group had 35.39 ± 17.17 days. A subset of three MRI features distinguished treatment effects starting from the first week with increasing accuracy throughout the treatment (75% to 94%). Besides, we observed that short-run emphasis of approximate wavelet coefficients had a positive correlation with the survival of the KPC mice (r = 0.78, p

PurposeTo evaluate the combination of 90Y radioembolization (Y90) and drug-eluting bead irinotecan (DEBIRI) microspheres in the VX2 rabbit model.Materials and methodsAn initial dose finding study was performed in 6 White New Zealand rabbits to identify a therapeutic but subcurative dose of Y90. In total, 29 rabbits were used in four groups: Y90 treatment (n = 8), DEBIRI treatment (n = 6), Y90 + DEBIRI treatment (n = 7), and an untreated control group (n = 8). Hepatic toxicity was evaluated at baseline, 24 h, 72 h, 1 week, and 2 weeks. MRI tumor volume (TV) and enhancing tumor volume were assessed baseline and 2 weeks. Tumor area and necrosis were evaluated on H&E for pathology.ResultsInfused activities of 84.0-94.4 MBq (corresponding to 55.1-72.7 Gy) were selected based on the initial dose finding study. Infusion of DEBIRI after Y90 was technically feasible in all cases (7/7). Overall, 21/29 animals survived to 2 weeks, and the remaining animals had extrahepatic disease on necropsy. Liver transaminases were elevated with Y90, DEBIRI, and Y90 + DEBIRI compared to control at 24 h, 72 h, and 1 week post-treatment and returned to baseline by 2 weeks. By TV, Y90 + DEBIRI was the only treatment to show statistically significant reduction at 2 weeks compared to the control group (p = 0.012). The change in tumor volume (week 2-baseline) for both Y90 + DEBIRI versus control (p = 0.002) and Y90 versus control (p = 0.014) was significantly decreased. There were no statistically significant differences among groups on pathology.ConclusionIntra-arterial Y90 + DEBIRI was safe and demonstrated enhanced antitumor activity in rabbit VX2 tumors. This combined approach warrants further investigation.

PurposeIrreversible electroporation (IRE) is a nonthermal tissue ablation technique that represents a promising treatment option for unresectable liver tumors, but the effectively treated zone cannot be reliably predicted. We investigate the potential benefit of transcatheter intra-arterial perfusion (TRIP) -MRI for the early noninvasive differentiation of IRE zone from surrounding reversibly electroporated (RE) zone.MethodsSeventeen rabbits with VX2 liver tumors were scanned with morphological and contrast-enhanced MRI sequences approximately 30 min after IRE tumor ablation. Quantitative TRIP-MRI perfusion parameters were evaluated in IRE zone and RE zone, defined according to histology. MRI and histology results were compared among zones using Wilcoxon rank-sum tests and correlations were evaluated by Pearson's correlation coefficient.ResultsThere were significant differences in area under the curve, time to peak, maximum and late enhancement, wash-in and wash-out rates in the tumor IRE zones compared with the boundary tumor RE zones and untreated tumors. Histology showed significantly fewer tumor cells, microvessels and significantly more apoptosis in tumor IRE zones compared with tumor RE zones (-51%, -66% and +185%, respectively) and untreated tumors (-60%, -67%, and +228%, respectively). A strong correlation was observed between MRI and histology measurements of IRE zones (r = 0.948) and RE zones (r = 0.951).ConclusionTRIP-MRI demonstrated the potential to detect immediate perfusion changes following IRE liver tumor ablation and effectively differentiate the IRE zone from the surrounding tumor RE zone.

The present study investigated if c-MYC and high mobility group AT-hook 2 (HMGA2) expression was associated with prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). A total of 102 patients undergoing surgery for PDAC were retrospectively reviewed. Immunohistochemistry was used to detect c-MYC and HMGA2 protein expression in PDAC and peritumoral tissue samples. Expression of c-MYC and HMGA2 was associated with clinicopathological characteristics and prognoses of patients with PDAC using multivariate analysis. HMGA2 and c-MYC protein expression was significantly higher in PDAC tissues compared with peritumoral tissue (P

BACKGROUND:We developed a computational model integrating clinical data and imaging features extracted from contrast-enhanced computed tomography (CECT) images, to predict lymph node (LN) metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS:This retrospective study included 159 patients with PDAC (118 in the primary cohort and 41 in the validation cohort) who underwent preoperative contrast-enhanced computed tomography examination between 2012 and 2015. All patients underwent surgery and lymph node status was determined. A total of 2041 radiomics features were extracted from venous phase images in the primary cohort, and optimal features were extracted to construct a radiomics signature. A combined prediction model was built by incorporating the radiomics signature and clinical characteristics selected by using multivariable logistic regression. Clinical prediction models were generated and used to evaluate both cohorts. RESULTS:Fifteen features were selected for constructing the radiomics signature based on the primary cohort. The combined prediction model for identifying preoperative lymph node metastasis reached a better discrimination power than the clinical prediction model, with an area under the curve of 0.944 vs. 0.666 in the primary cohort, and 0.912 vs. 0.713 in the validation cohort. CONCLUSIONS:This pilot study demonstrated that a noninvasive radiomics signature extracted from contrast-enhanced computed tomography imaging can be conveniently used for preoperative prediction of lymph node metastasis in patients with PDAC.

It is unknown whether the route of administration impacts dendritic cell (DC)-based immunotherapy for pancreatic ductal adenocarcinoma (PDAC). We compared the effect of intraperitoneal (i.p.), subcutaneous (s.c.), and intratumoral (i.t.) administration of DC vaccine on induction of antitumor responses in a KPC mouse model of PDAC. Histological analysis and flow cytometry were used to evaluate tumor progression and antitumor immunity after different routes of DC vaccination. Using a flank mouse model of PDAC, we found that the i.t. route of DC vaccination had no significant effect on tumor growth rates compared with i.p. and s.c. routes (i.p. 6.66 ± 2.58% vs s.c. 6.79 ± 1.36% vs i.t. 8.57 ± 2.36%; P = 0.33). However, in an orthotopic PDAC model, i.p. injection of DC vaccine effectively suppressed tumor growth, inhibited tumor progression, and increased antitumor immunity compared with s.c. vaccination (tumor weight: i.p. 71.60 ± 15.55 mg vs control 200.40 ± 53.04 mg; P = 0.048; s.c. 151.40 ± 41.64 mg vs control 200.40 ± 53.04 mg; P = 0.49). Our study suggests that immunization via an i.p. route results in superior antitumor immune response and tumor suppression when compared with other routes.

Dinaciclib is a small molecule cyclin-dependent kinase inhibitor with the potential to treat multiple cancers. To better understand its cytotoxic action in pancreatic ductal adenocarcinoma (PDAC), we evaluated dinaciclib therapeutic effects in the transgenic mouse model (LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre mice; KPC mice). Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Dinaciclib therapy significantly delayed tumor progression (P < 0.001) and prolonged survival (P = 0.007) in KPC mice. In vitro assays showed that dinaciclib exerted antiproliferative effects on PDAC cells by increasing surface calreticulin expression and release of ATP. Dinaciclib treatment inhibited proliferation and induced apoptosis in KPC tumor as assessed by Ki67 and cleaved caspase 3, respectively. Particularly, the tumor infiltrating CD8+ T cells were increased after dinaciclib treatment in KPC mice. Additionally, the mean apparent diffusion coefficient values of KPC tumor calculated from diffusion weighted MR images were significantly lower after dinaciclib treatment (P = 0.033). These finding suggest that dinaciclib as a single agent can inhibit tumor growth and improve the overall survival in KPC mice.

There is a lack of a well-established approach for assessment of early treatment outcomes for modern therapies for pancreatic ductal adenocarcinoma (PDAC) e.g. dinaciclib or dendritic cell (DC) vaccination. Here, we developed multivariate models using MRI texture features to detect treatment effects following dinaciclib drug or DC vaccine therapy in a transgenic mouse model of PDAC including 21 LSL-KrasG12D ; LSL-Trp53R172H ; Pdx-1-Cre (KPC) mice used as untreated control subjects (n=8) or treated with dinaciclib (n=7) or DC vaccine (n=6). Support vector machines (SVM) technique was performed to build a linear classifier with three variables for detection of tumor tissue changes following drug or vaccine treatments. Besides, multivariate regression models were generated with five variables to predict survival behavior and histopathological tumor markers (Fibrosis, CK19, and Ki67). The diagnostic performance was evaluated using accuracy, area under the receiver operating characteristic curve (AUC) and decision curve analyses. The regression models were evaluated with adjusted r-squared (Radj 2). SVM classifier successfully distinguished changes in tumor tissue with an accuracy of 95.24% and AUC of 0.93. The multivariate models generated with five variables were strongly associated with histopathological tumor markers, fibrosis (Radj 2=0.82, P

PurposeIrreversible electroporation (IRE) is a promising new ablation method for hepatocellular carcinoma (HCC) treatment with few side-effects; however, tissue perfusion and differentiation between treatment zones have not been sufficiently studied. In this project, we analyzed HCC tumor perfusion changes immediately after IRE treatment using transcatheter intraarterial perfusion (TRIP)-MRI to monitor treatment zone margins.Materials and methodsAll protocols were approved by the institutional animal care and use committee. A total of 34 rabbits were used for this prospective study: tumor liver group (n=17), normal liver group (n=14), and 3 for growing VX2 tumors. All procedures and imaging were performed under anesthesia. VX2 tumors were grown by injection of VX2 cells into rabbit hindlimbs. Liver tumors were induced by percutaneous US-guided injection of VX2 tumor fragments into liver. For digital subtraction angiography (DSA), a 2F catheter was advanced through left hepatic artery via femoral artery access, followed by contrast injection. All rabbits underwent baseline anatomic MRI, then IRE procedure or IRE probe placement only, and lastly post-procedure anatomic and TRIP-MRI. Liver tissues were dissected immediately after imaging for histology. All statistical analyses were performed on GraphPad Prism, with P

The contractile protein MYH9 (non-muscle myosin IIA) is an actin-binding protein that plays a fundamental role in cell adhesion, migration, and division. However, its distinct role in colorectal cancer (CRC) still remains unidentified. In this study, we detected significant MYH9 overexpression in CRC samples compared with paired normal tissues using western blotting and tissue microarray immunohistochemistry (IHC). Moreover, analysis of patient clinical information demonstrated that MYH9 overexpression was strongly correlated with lymph node metastasis and poor overall survival. Endogenous overexpression of MYH9 enhanced the ability of cell proliferation and migration in vitro, and accelerated CRC growth in mouse models. Silencing of MYH9 revealed repressive effects on CRC cells in vitro and in vivo. Furthermore, primary biomechanics that involved MAPK/AKT signaling mediated epithelial-mesenchymal transition (EMT) was uncovered underlying MYH9 dependent cell behaviors. Collectively, our data showed that MYH9 significantly promoted tumorigenesis by regulating MAPK/AKT signaling, and was remarkably correlated with poor prognosis in CRC. MYH9 may thus be a novel biomarker and drug target in the diagnosis and treatment of CRC.

As the major thermogenic tissue in body, the brown adipose tissue (BAT) was recently identified as an important factor to induce the rapid weight loss and malnutrition in malignancy. Current methods for detecting and quantifying brown adipose tissue (BAT) are in limited use. The aim of this study was to evaluate the changes of BAT tissue and its function in the development of pancreatic ductal adenocarcinoma (PDAC) by using magnetic resonance imaging (MRI). Ten-week-old female C57BL/6 mice were inoculated orthotopically with Pan02 tumor cells. R2* maps and two-point Dixon MRI were performed weekly for evaluation of BAT function and volume, respectively. The T2-weighted MRI was applied weekly for monitoring tumor growth. Meanwhile, the body weight was measured daily as another indication of malnutrition. The UCP1 levels in BAT and white adipose tissue (WAT) were assessed. The serum IL-6 was also measured as the biomarker of cancer-associated cachexia. T2-weighted MRI indicated the rapid tumor growth from week 3 to week 5 after tumor cell inoculation. The water-fat separated MRI could clearly identify and quantify the BAT. The function and volume of BAT could be monitored by weekly MRI measurement in tumor-bearing mice. The total body weights of PDAC tumor-bearing mice were relatively stable, however, was significantly lower than that of control C57BL/6 mice. The results of this study demonstrated the feasibility of detection and quantification of BAT in vivo by MRI during the development of pancreatic cancer.

The purpose of our study was to investigate the hypothesis that DWI-MRI and DCE-MRI cab be used to distinguish between IRE and RE zones of IRE treatment in a rabbit liver model. 6 rabbits underwent baseline and post-procedure MR imaging with DWI and DCE-MRI as well as IRE (10 pulses, 2000 V, 10 µs/pulse, 10 ms between pulses). Rabbits were euthanized immediately after post-procedure MRI to acquire liver tissue for histology. Liver tissues were fixed and then stained with HE and TUNEL. T1w and T2w intensities in different treatment zones were calculated and normalized to paraspinal muscle signal. ADC maps were generated from DWI. AUC, PE, TTP, WIS, Ktrans, Kep, and VE were calculated from DCE-MRI. Apoptosis index was calculated from TUNEL stained tissues. P

The aim of this study was to develop and validate a new non-invasive artificial intelligence (AI) model based on preoperative computed tomography (CT) data to predict the presence of liver metastasis (LM) in colon cancer (CC). A total of forty-eight eligible CC patients were enrolled, including twenty-four patients with LM and twenty-four patients without LM. Six clinical factors and one hundred and fifty-two tumor image features extracted from CT data were utilized to develop three models: clinical, radiomics, and hybrid (a combination of clinical and radiomics features) using support vector machines with 5-fold cross-validation. The performance of each model was evaluated in terms of accuracy, specificity, sensitivity, and area under the curve (AUC). For the radiomics model, a total of four image features utilized to construct the model resulting in an accuracy of 83.87% for training and 79.50% for validation. The clinical model that employed two selected clinical variables had an accuracy of 69.82% and 69.50% for training and validation, respectively. The hybrid model that combined relevant image features and clinical variables improved accuracy of both training (90.63%) and validation (85.50%) sets. In terms of AUC, hybrid (0.96; 0.87) and radiomics models (0.91; 0.85) demonstrated a significant improvement compared with the clinical model (0.71; 0.69), and the hybrid model had the best prediction performance. In conclusion, the AI model developed using preoperative conventional CT data can accurately predict LM in CC patients without additional procedures. Furthermore, combining image features with clinical characteristics greatly improved the model's prediction performance. We have thus generated a promising tool that allows guidance and individualized surveillance of CC patients with high risks of LM.

The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. However, long-term benefits of DC vaccination are reported in only scattered patients with pancreatic ductal adenocarcinoma (PDAC). Here we optimize DC vaccination and evaluate its safety and antitumor efficacy in the genetically engineered PDAC model (KrasLSL-G12D p53LSL-R172H Pdx-1-Cre (KPC mice)). KPC transgenic mice and orthotopic models using KPC cell lines were treated with DC vaccine via an intraperitoneal route. Tumor growth and microenvironment were dynamically monitored by magnetic resonance imaging (MRI). Histological analysis and flow cytometry were used to evaluate tumor-directed T cell immunity of these mice. DC vaccine via intraperitoneal injection suppressed tumor progression (P = 0.030) and significantly prolonged survival time (P = 0.028) in KPC mice. Vaccinated KPC mice displayed an increased antitumor T cell response indicated by a higher IFN-γ production (P = 0.016) and tumor-specific cytotoxicity (P = 0.027). Particularly, the mean apparent diffusion coefficient (ADC) values of KPC tumor calculated from diffusion weighted MRI (DW-MRI) were significantly higher in DC vaccine group than that in control group (P < 0.001). More interestingly, we observed that ADC positively correlated with fibrosis in KPC tumor (R2 = 0.463, P = 0.015). Our study demonstrated that the immunization with our improved DC vaccine can elicit a strong tumor-specific immune response and tumor suppression in PDAC.

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

BACKGROUND:Post-infarction cardiovascular remodeling and heart failure are the leading cause of myocardial infarction (MI)-driven death during the past decades. Experimental observations have involved intestinal microbiota in the susceptibility to MI in mice; however, in humans, identifying whether translocation of gut bacteria to systemic circulation contributes to cardiovascular events post-MI remains a major challenge. RESULTS:Here, we carried out a metagenomic analysis to characterize the systemic bacteria in a cohort of 49 healthy control individuals, 50 stable coronary heart disease (CHD) subjects, and 100 ST-segment elevation myocardial infarction (STEMI) patients. We report for the first time higher microbial richness and diversity in the systemic microbiome of STEMI patients. More than 12% of post-STEMI blood bacteria were dominated by intestinal microbiota (Lactobacillus, Bacteroides, and Streptococcus). The significantly increased product of gut bacterial translocation (LPS and D-lactate) was correlated with systemic inflammation and predicted adverse cardiovascular events. Following experimental MI, compromised left ventricle (LV) function and intestinal hypoperfusion drove gut permeability elevation through tight junction protein suppression and intestinal mucosal injury. Upon abrogation of gut bacterial translocation by antibiotic treatment, both systemic inflammation and cardiomyocyte injury in MI mice were alleviated. CONCLUSIONS:Our results provide the first evidence that cardiovascular outcomes post-MI are driven by intestinal microbiota translocation into systemic circulation. New therapeutic strategies targeting to protect the gut barrier and eliminate gut bacteria translocation may reduce or even prevent cardiovascular events post-MI.

BackgroundThe aim of this study was to compare intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) parameters such as standard apparent diffusion coefficient (ADCstandard), pure diffusion coefficient (Dslow), pseudodiffusion coefficient (Dfast) and perfusion fraction (ƒ) for differentiating pancreatic ductal adenocarcinoma (PDAC) with different pathological grades.MethodsInstitutional Review Board of our hospital approved this study protocol. Subjects comprised 38 PDACs confirmed by pathology. Pancreatic multiple b values DWI with 15 b values of 0, 10, 20, 40, 60, 80, 100, 150, 200, 400, 800, 1,000, 1200, 1,500, and 2,000 s/mm2 was performed using GE Discovery MR750 3.0T scanner. ADCstandard, Dslow, Dfast and ƒ values of all PDACs were calculated using mono- and bi-exponential models. Parameters of well/moderately differentiated and poorly differentiated PDAC were compared using Independent Sample t-test. P values 0.865). When the Dslow value was less than or equal to 0.599×10-3 mm2/s, the sensitivity and specificity were 100% and 84.6% respectively. When ƒ value was greater than 49.6%, the sensitivity and specificity were 92.0% and 84.6% respectively.ConclusionsDslow and ƒ derived from IVIM-DWI model can be used to distinguish well/moderately differentiated PDAC from poorly differentiated PDAC. And to serve this purpose, Dslow and ƒ have high diagnostic performance. IVIM-DWI is a promising and non-invasive tool for predicting pathological grade of PDAC.

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.

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.

The efficacy and safety of combining open-configuration magnetic resonance imaging (MRI) and an optical surgical navigation system (OSNS) for guidance of percutaneous liver cryoablation were evaluated in a pig model. This approach was successfully executed in eight test pigs under general anesthesia. Another two pigs spared from ablation served as controls. MRI studies, blood testing, and pathologic examinations were performed at various time points. MRI-determined minimal and maximal cryolesion diameters were 19.4 ± 1.5 mm and 44.3 ± 1.8 mm, respectively (mean volume, 8.32 ± 2.41 cm3). The lesions were readily visible by MRI on postablation Days 2 and 7, all presenting as teardrop-shaped regions of low signal intensity in T1-weighted images and high signal intensity in T2-weighted images. Mean serum alanine aminotransferase concentration transiently increased postablation, and mean blood platelet count transiently declined (both, P < 0.05). The mean necrotic tissue volume generated by pathologic assessment was less than that determined by MRI (4.24 ± 2.3 cm3 vs. 8.32 ± 2.41 cm3, P < 0.05). Cell necrosis isotherms in MRI views were within 6.0 ± 0.8 mm of cryolesion edges. Inflammatory cell infiltrates and exuberant granulation tissue surrounded necrotic areas on postablation Day 7. Combined open-configuration MRI and OSNS guidance of percutaneous liver cryoablation proved effective and safe in our animal model. This concept seems ideal for precision image-guided hepatic ablation in a clinical setting.

BackgroundLiver 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.MethodsThis 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.ResultsIn 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.ConclusionAlthough 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.

Dendritic cells (DCs) are the most potent antigen-presenting cells, and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes (CTLs) in lymphatic tissues. DC vaccination is a newly emerging and potent form of cancer immunotherapy and has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The efficacy of DC-vaccines is strongly influenced by various techniques for the priming antigen loading onto DCs and their ability to migrate to the draining lymph nodes (LNs). Therefore, it is critical to improve DC-vaccines homing to draining LNs after administration in order to optimize DC-based therapy for individual patients. This review underlines 1) appropriate strategy to load tumor antigens onto DCs and 2) to optimize vaccine administration methods to ensure loaded DCs can migrate to LNs, in particular, Intraperitoneal (IP) injection. IP injection of DC-based vaccine may be a potential regimen for gastrointestinal tumors including hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PDAC) since huge populations of LNs are present throughout the gastrointestinal track. Which might improve the subsequent migration to LNs.

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.

A modern multi-functional drug carrier is critically needed to improve the efficacy of image-guided catheter-directed approaches for the treatment of hepatic malignancies. For this purpose, a nanocomposite microsphere platform was developed for selective intra-arterial transcatheter drug delivery to liver tumors. In our study, continuous microfluidic methods were used to fabricate drug-loaded multimodal MRI/CT visible microspheres that included both gold nanorods and magnetic clusters. The resulting hydrophilic, deformable, and non-aggregated microspheres were mono-disperse and roughly 25 um in size. Sustained drug release and strong MRI T2 and CT contrast effects were achieved with the embedded magnetic nano-clusters and radiopaque gold nanorods. The microspheres were successfully infused through catheters selectively placed within the hepatic artery in rodent models and subsequent distribution in the targeted liver tissues and hepatic tumors confirmed with MRI and CT imaging. These multimodal nanocomposite drug carriers should be ideal for selective intra-arterial catheter-directed administration to liver tumors while permitting MRI/CT visualization for patient-specific confirmation of tumor-targeted delivery.

PurposeTo investigate the qualitative and quantitative impacts of labeling yttrium microspheres with increasing amounts of superparamagnetic iron oxide (SPIO) material for magnetic resonance (MR) imaging in phantom and rodent models.Materials and methodsAnimal model studies were approved by the institutional Animal Care and Use Committee. The r2* relaxivity for each of four microsphere SPIO compositions was determined from 32 phantoms constructed with agarose gel and in eight concentrations from each of the four compositions. Intrahepatic transcatheter infusion procedures were performed in rats by using each of the four compositions before MR imaging to visualize distributions within the liver. For quantitative studies, doses of 5, 10, 15, or 20 mg 2% SPIO-labeled yttrium microspheres were infused into 24 rats (six rats per group). MR imaging R2* measurements were used to quantify the dose delivered to each liver. Pearson correlation, analysis of variance, and intraclass correlation analyses were performed to compare MR imaging measurements in phantoms and animal models.ResultsIncreased r2* relaxivity was observed with incremental increases of SPIO microsphere content. R2* measurements of the 2% SPIO-labeled yttrium microsphere concentration were well correlated with known phantom concentrations (R(2) = 1.00, P < .001) over a broader linear range than observed for the other three compositions. Microspheres were heterogeneously distributed within each liver; increasing microsphere SPIO content produced marked signal voids. R2*-based measurements of 2% SPIO-labeled yttrium microsphere delivery were well correlated with infused dose (intraclass correlation coefficient, 0.98; P < .001).ConclusionMR imaging R2* measurements of yttrium microspheres labeled with 2% SPIO can quantitatively depict in vivo intrahepatic biodistribution in a rat model.

This study aimed to determine whether changes in contrast-enhanced computed tomography (CT) parameters could predict postsurgery overall and progression-free survival (PFS) in pancreatic cancer patients. Seventy-nine patients with a final pathological diagnosis of pancreatic adenocarcinoma were included in this study from June 2008 to August 2012. Dynamic contrast-enhanced (DCE) CT of tumors was obtained before curative-intent surgery. Absolute enhancement change (AEC) and relative enhancement change (REC) were evaluated on DCE-CT. PFS and overall survival (OS) were compared based on CT enhancement patterns. The markers of fibrogenic alpha-smooth muscle antigen (α-SMA) and periostin in tumor specimens were evaluated by immunohistochemical staining. The χ test was performed to determine whether CT enhancement patterns were associated with α-SMA-periostin expression levels (recorded as positive or negative). Lower REC (

This study aimed to determine the relationships between magnetic resonance elastography (MRE) imaging biomarkers and the stages of liver fibrosis in a rabbit model of liver fibrosis, a longitudinal validation for clinical translation. Liver fibrosis was induced in 38 male New Zealand rabbits by weekly subcutaneous injections of 0.1 ml 50% carbon tetrachloride oily solution per kilogram of body weight for 4 to 10 weeks to produced varying degrees of liver fibrosis. The values for the liver stiffness (LS) MRE imaging biomarkers were measured at different stages of liver fibrosis. Masson trichrome staining of liver tissue was used to identify collagen tissue. Among the 38 rabbits, the histological studies showed liver fibrosis stage 1 (F1, n = 11), liver fibrosis stage 2 (F2, n = 8), liver fibrosis stage 3 (F3, n = 7), and liver fibrosis stage 4 (F4, liver cirrhosis, n = 12). Additional healthy rabbits served as controls (F0, n = 15). During liver fibrosis progression, the mean LS values increased during liver fibrosis progression. There were significant differences in LS values between (F0 and F1) and (F2 and F3), (F2 and F3) and (F4), and (F0 and F1) and (F4), which are three clinically relevant fibrosis groups. There was a high correlation between the LS values measured by MRE and the stages of liver fibrosis determined by histology (R2 = 0.67, P < 0.001). MRE imaging has the potential to serve as a noninvasive, unenhanced imaging technique for liver fibrosis diagnosis and staging.

The present study aimed to evaluate the feasibility of performing carbogen gas-challenge blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) measurements in patients with hepatocellular carcinoma (HCC). A total of 25 patients with HCC underwent T2* mapping derived from multi-echo gradient-recalled echo imaging prior to and following breathing carbogen (95% O2 and 5% CO2) for 10 min. Follow-up T2* mapping was performed in 5 patients 1 day after transarterial chemoembolization (TACE). T2*, R2* and ∆R2* values (R2*air - R2*carb) of the whole tumor, the solid region of the tumor and the adjacent liver parenchyma were measured and compared in the patients with HCC. The T2* value of the solid region of the tumor following carbogen breathing was higher than the value following room air breathing (P

PurposeMagnetization transfer (MT) MRI can be effective for the diagnosis of a broad range of fibrotic diseases, including liver fibrosis. However, respiratory motion, a major source of artifacts in thoracic and abdominal MR imaging, can obscure important anatomic structures, making diagnosis difficult. In this study, we explored the potential to combine free-breathing (FB) respiratory self-gating (RSG) methods with MT saturation for FB MT ratio (MTR) measurements of abdominal organs.MethodsA respiratory self-gated multiple-gradient recalled echo sequence with MT presaturation (RSG-MT GRE) was developed and applied in a series of seven normal volunteers. We compared the MTR values of liver, pancreas, kidney, spleen, and posterior paraspinal muscle measured using our RSG-MT GRE sequence and a conventional MT GRE sequence.ResultsRSG consistently reduced motion artifacts within MT-weighted images acquired during FB, improved the accuracy of FB MTR measurements, and produced comparable MTRs to breath-holding MTR measurements.ConclusionRSG approaches may offer to improve the utility of MT-weighted imaging methods for the assessment of fibrotic diseases and tumor desmoplasia in abdominal organs.

ObjectiveTo demonstrate feasibility of performing quantitative MRI measurements in an immuno-competent rat model of pancreatic cancer by comparing in vivo anatomic and quantitative imaging measurements to tumor dissemination observations and histologic assays at necropsy. Meterials and methods: Rat ductal pancreatic adenocarcinoma DSL-6A/C1 cell line and Lewis rats were used for these studies. 10(8) DSL-6A/C1 cells were injected subcutaneously into the right flank of donor rats. Donor tumors reaching 10 mm were excised, and 1 mm(3) tumor fragments were implanted within recipient rat pancreas during mini-laparotomy. T1-weighted, T2-weighted, diffusion-weighted, and dynamic contrast-enhanced (DCE) MRI were performed using a Bruker 7.0T ClinScan. After MRI, all animals underwent autopsy. Primary tumor size was measured, and dissemination score was used to assess local invasion and distant metastasis. Primary tumor and all sites of metastases were harvested and fixed for H&E, Masson's trichrome, and rat anti-CD34 staining. Trichrome slides were scanned and digitized for measurement of fibrotic tissue areas. Anti-CD34 slides were used for microvessel density (MVD) measurements.ResultsPrimary tumors, local invasion, and distant metastases were confirmed for all rats. No significant differences were found between in vivo MRI measurements (48.7 ± 5.3 mm) and ex vivo caliper measurements (43.6 ± 3.6 mm) of primary tumor sizes (p > .05). Spleen, liver, diaphragm, peritoneum, and abdominal wall metastases were observed on MRI but smaller lung, mediastinum, omen, and mesentery metastases were only observed at necropsy. Contrast uptake observed during DCE measurements was significantly greater in both primary and metastatic tumor tissues compared to skeletal muscle and normal liver tissues. Both primary and metastatic tumors were hyper-intense in T2-weighted images and hypo-intense in T1-weighted images, but no differences were found between quantitative T2 measurements in primary tumors and that in metastases. Similarly, quantitative ADC measurements were similar for both primary tumor and liver metastases (1.13 ± 0.3 × 10(-3) and 1.24 ± 0.4 × 10(-3) mm(2)/s, respectively). Histologic fibrosis and MVD measurements were similar in primary tumors and metastases.ConclusionsAnatomic and quantitative functional MRI measurements are feasible in orthotropic DSL rat model and will permit non-invasive monitoring of tumor responses during longitudinal studies intended to develop new interventional therapies for primary and metastatic disease.

AimTo test the hypothesis that MRI can monitor intraportal vein (IPV) transcatheter delivery of clinically applicable heparin-protamine-ferumoxytol (HPF) nanocomplex-labeled natural killer (NK) cells to liver tumor.Materials & methodsLiver tumor rat models underwent catheterization for IPV infusion of HPF-labeled NK cells (NK-92MI cell line). MRI measurements within tumor and adjacent liver tissues were compared pre- and post-NK cell infusion. Histology studies were used to identify NK cells in the target tumors.ResultsFor first time, we demonstrated that MRI tracks HPF-labeled NK cells migration within liver following IPV delivery.ConclusionIPV transcatheter infusion permitted selective delivery of NK cells to liver tissues and MRI allowed tracking NK cell biodistributions within the tumors.

The multi-kinase inhibitor (MKI) sorafenib can be an effective palliative therapy for patients with hepatocellular carcinoma (HCC). However, patient tolerance is often poor due to common systemic side effects following oral administration. Local transcatheter delivery of sorafenib to liver tumors has the potential to reduce systemic toxicities while increasing the dose delivered to targeted tumors. We developed sorafenib-eluting PLG microspheres for delivery by intra-hepatic transcatheter infusion in an orthotropic rodent HCC model. The particles also encapsulated iron-oxide nanoparticles permitting magnetic resonance imaging (MRI) of intra-hepatic biodistributions. The PLG microspheres (diameter≈1μm) were loaded with 18.6% (w/w) sorafenib and 0.54% (w/w) ferrofluid and 65.2% of the sorafenib was released within 72h of media exposure. In vitro studies demonstrated significant reductions in HCC cell proliferation with increasing doses of the sorafenib-eluting microspheres, where the estimated IC50 was a 29μg/mL dose of microspheres. During in vivo studies, MRI permitted intra-procedural visualization of intra-hepatic microsphere delivery. At 72h after microsphere infusion, microvessel density was significantly reduced in tumors treated with the sorafenib-eluting microspheres compared to both sham control tumors (by 35%) and controls (by 30%). These PLG microspheres offer the potential to increase the efficacy of molecularly targeted MKI therapies while reducing systemic exposures via selective catheter-directed delivery to HCC.

PurposeTo compare changes on ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) images after irreversible electroporation (IRE) ablation of liver and tumor tissues in a rodent hepatoma model.Materials and methodsStudies received approval from the institutional animal care and use committee. Forty-eight rats were used, and N1-S1 tumors were implanted in 24. Rats were divided into groups and allocated for studies with each modality. Imaging was performed in normal liver tissues and tumors before and after IRE. MR imaging was performed in one group before and after IRE after hepatic vessel ligation. US images were graded to determine echogenicity changes, CT attenuation was measured (in Hounsfield units), and MR imaging signal-to-noise ratio (SNR) was measured before and after IRE. Student t test was used to compare attenuation and SNR measurements before and after IRE (P < .05 indicated a significant difference).ResultsIRE ablation produced greater alterations to echogenicity in normal tissues than in tumors. Attenuation in ablated liver tissues was reduced compared with that in control tissues (P < .001), while small attenuation differences between ablated (42.11 HU ± 2.11) and control (45.14 HU ± 2.64) tumors trended toward significance (P = .052). SNR in ablated normal tissues was significantly altered after IRE (T1-weighted images: pre-IRE, 145.95 ± 24.32; post-IRE, 97.80 ± 18.03; P = .004; T2-weighted images, pre-IRE, 47.37 ± 18.31; post-IRE, 90.88 ± 37.15; P = .023). In tumors, SNR differences before and after IRE were not significant. No post-IRE signal changes were observed after hepatic vessel ligation.ConclusionIRE induces rapid changes on gray-scale US, unenhanced CT, and MR images. These changes are readily visible and may assist a performing physician to delineate ablation zones from the unablated surrounding parenchyma.

To improve the efficacy of gemcitabine (GEM) for the treatment of advanced pancreatic cancer via local hyperthermia potentiated via a multi-functional nanoplatform permitting both in vivo heating and drug delivery is the goal of this study. Here, a chemohyperthermia approach to synergistically achieve high intra-tumoral drug concentrations, while permitting concurrent hyperthermia for more effective tumor cell kill and growth inhibition, is proposed. Drug delivery and hyperthermia are achieved using a hydroxypropyl cellulose (HPC)-grafted porous magnetic drug carrier that is MRI visible to permit in vivo visualization of the biodistribution. These synthesized magnetic drug carriers produce strong T2 -weighted image contrast and permit efficient heating using low-magnetic-field intensities. The thermomechanical response of HPC permits triggered GEM release confirmed during in vitro drug release studies. During in vitro studies, pancreatic cancer cell growth is significantly inhibited (≈82% reduction) with chemohyperthermia compared to chemotherapy or hyperthermia alone. Using PANC-1 xenografts in nude mice, the delivery of injected GEM-loaded magnetic carriers (GEM-magnetic carriers) is visualized with both MRI and fluorescent imaging techniques. Chemohyperthermia with intra-tumoral injections of GEM-magnetic carriers (followed by heating) results in significant increases in apoptotic cell death compared to tumors treated with GEM-magnetic carriers injections alone. Chemohyperthermia with GEM-magnetic carriers offers the potential to significantly improve the therapeutic efficacy of GEM for the treatment of pancreatic cancer. In vivo delivery confirmation with non-invasive imaging techniques could permit patient-specific adjustments therapeutic regimens for improve longitudinal outcomes.

AimNanoKnife(®) (Angiodynamics, Inc., NY, USA) or irreversible electroporation (IRE) is a newly available ablation technique to induce the formation of nanoscale pores within the cell membrane in targeted tissues. The purpose of this study was to elucidate morphological alterations following 30 min of IRE ablation in a mouse model of pancreatic cancer.Materials & methodsImmunohistochemistry markers were compared with diffusion-weighted MRI apparent diffusion coefficient measurements before and after IRE ablation.ResultsImmunohistochemistry apoptosis index measurements were significantly higher in IRE-treated tumors than in controls. Rapid tissue alterations after 30 min of IRE ablation procedures (structural and morphological alterations along with significantly elevated apoptosis markers) were consistently observed and well correlated to apparent diffusion coefficient measurements.DiscussionThis imaging assay offers the potential to serve as an in vivo biomarker for noninvasive detection of tumor response following IRE ablation.

ObjectivesTo validate the feasibility of labeling Clostridium novyi-NT (C.novyi-NT) anaerobes with iron-oxide nanoparticles for magnetic resonance imaging (MRI) and demonstrate the potential to use MRI to visualize intra-tumoral delivery of these iron-oxide labeled C.novyi-NT during percutaneous injection procedures.Materials and methodsAll studies were approved by IACUC. C.novyi-NT were labeled with hybrid iron-oxide Texas red nanoparticles. Growth of labeled and control samples were evaluated with optical density. Labeling was confirmed with confocal fluorescence and transmission electron microscopy (TEM). MRI were performed using a 7 Tesla scanner with T2*-weighted (T2*W) sequence. Contrast-to-noise ratio (CNR) measurements were performed for phantoms and signal-to-noise ratio (SNR) measurements performed in C57BL/6 mice (n = 12) with Panc02 xenografts before and after percutaneous injection of iron-oxide labeled C.novyi-NT. MRI was repeated 3 and 7 days post-injection. Hematoxylin-eosin (HE), Prussian blue and Gram staining of tumor specimens were performed for confirmation of intra-tumoral delivery.ResultsIron-oxide labeling had no influence upon C.novyi-NT growth. The signal intensity (SI) within T2*W images was significantly decreased for iron-oxide labeled C.novyi-NT phantoms compared to unlabeled controls. Under confocal fluorescence microscopy, the iron-oxide labeled C.novyi-NT exhibited a uniform red fluorescence consistent with observed regions of DAPI staining and overall labeling efficiency was 100% (all DAPI stained C.novyi-NT exhibited red fluorescence). Within TEM images, a large number iron granules were observed within the iron-oxide labeled C.novyi-NT; these were not observed within unlabeled controls. Intra-procedural MRI measurements permitted in vivo visualization of the intra-tumoral distribution of iron-oxide labeled C.novyi-NT following percutaneous injection (depicted as punctate regions of SI reductions within T2*-weighted images); tumor SNR decreased significantly following intra-tumoral injection of C.novyi-NT (p

Quantitative assessment of desmoplasia in pancreatic ductal adenocarcinoma (PDAC) may be critical for staging or prediction of response to therapy. We performed quantitative magnetization transfer (qMT) MRI measurements in 18 mouse xenograft tumors generated from three PDAC cell lines. The qMT parameter bound proton fraction (BPF) was found to be significantly higher in tumors grown using the BxPC-3 cell line (5.31 ± 0.87, mean ± standard deviation) compared with the BPF measured for tumors grown from Panc-1 (3.65 ± 0.60) and Capan-1 (1.50 ± 0.58) cell lines (P < 0.05 for each comparison). Histologic measurements demonstrated a similar trend; BxPC-3 tumors had significantly higher fibrosis levels (percentage of fibrotic tissue area, 6.21 ± 2.10) compared with Panc-1 (2.88 ± 1.13) and Capan-1 (1.69 ± 1.01) tumors. BPF was well correlated with quantitative fibrosis levels (r = 0.77, P < 0.01). Our results indicate that qMT measurements offer the potential to noninvasively quantify fibrosis levels in PDAC mouse xenograft models and thus serve as a valuable in vivo biomarker of desmoplasia in PDAC.