Hepatocellular carcinoma (HCC) is the third most frequent source of deaths associated with cancer after lung cancer in the world despite recent innovative treatment techniques. Liver transplantation, hepatic resection, and percutaneous ablation techniques hold great promise as potentially curative treatments for patients at early stages. Nevertheless, most of the patients are not suitable for these curative treatments due to their advanced disease stages at the time of diagnosis. Food and Drug Administration (FDA) approved tyrosine kinase inhibitor, sorafenib is a standard therapy for advanced-stage HCC patients which extends overall survival for several months. However, its therapeutic efficacy is restricted by adverse events and drug resistance which limits the number of patients benefiting from this systemic chemotherapeutic drug. During the last decade, novel approaches including but not limited to immunotherapies, ablation methods, and chemotherapeutic drugs were proposed to enhance sensitivity to sorafenib, improve therapeutic efficacy, and prohibit adverse events through novel delivery routes, utilization of nanoparticle carriers, and combination with other therapeutic agents. However, studies are still being conducted to optimize the efficiency of sorafenib and reduce its adverse events. In this review paper, we examine research studies evaluating novel delivery methods to reduce drug-related cytotoxicity to improve patient tolerance to sorafenib and its therapeutic efficacy in patients with HCC. Moreover, therapeutic approaches with the synergistic potential to combine with sorafenib are briefly summarized.

There is a great demand for accurate non-invasive measures to better define the natural history of disease progression or treatment outcome in Duchenne muscular dystrophy (DMD) and to facilitate the inclusion of a large range of participants in DMD clinical trials. This review aims to investigate which MRI sequences and analysis methods have been used and to identify future needs. Medline, Embase, Scopus, Web of Science, Inspec, and Compendex databases were searched up to 2 November 2019, using keywords magnetic resonance imaging and Duchenne muscular dystrophy. The review showed the trend of using T1w and T2w MRI images for semi-qualitative inspection of structural alterations of DMD muscle using a diversity of grading scales, with increasing use of T2map, Dixon, and MR spectroscopy (MRS). High-field (>3T) MRI dominated the studies with animal models. The quantitative MRI techniques have allowed a more precise estimation of local or generalized disease severity. Longitudinal studies assessing the effect of an intervention have also become more prominent, in both clinical and animal model subjects. Quality assessment of the included longitudinal studies was performed using the Newcastle-Ottawa Quality Assessment Scale adapted to comprise bias in selection, comparability, exposure, and outcome. Additional large clinical trials are needed to consolidate research using MRI as a biomarker in DMD and to validate findings against established gold standards. This future work should use a multiparametric and quantitative MRI acquisition protocol, assess the repeatability of measurements, and correlate findings to histologic parameters.

Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver, which is considered the fourth leading cause of cancer-related death in the United States. Liver transplant and surgical resection are curative treatments for HCC, but only 10-15% of HCC patients are eligible candidates. The FDA-approved sorafenib is a multi-kinase inhibitor systemic therapy for advanced HCC that extends the overall survival by over 3 months when compared with placebo. Adoptive transfer of Natural Killer (NK) cells holds great promise for clinical cancer treatment. However, only limited clinical benefit has been achieved in cancer patients. Therefore, there is currently considerable interest in development of the combination of sorafenib and NK cells for the treatment of HCC patients. However, the mechanism of how sorafenib affects the function of NK cells remains to be comprehensively clarified. In this paper, we will discuss NK cell-based immunotherapies that are currently under preclinical and clinical investigation and its potential combination with sorafenib for improving the survival of HCC patients.

Rationale and objectives

To 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-Kras^G12D; LSL-Trp53^R172H; Pdx-1-Cre (KPC) transgenic mice model of pancreatic ductal adenocarcinoma.

Materials and methods

Eight 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.

Results

The 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) <6 days. The proposed multivariate regression models predicted histological tumor markers with relative error <2.5% for fibrosis percentage (RMSE: 0.414), CK19⁺ area (RMSE: 0.027), and Ki67⁺ cells (RMSE: 0.190).

Conclusion

Our results demonstrated that proposed models generated with quantitative MRI features can be used to detect early treatment-related changes in tumor tissue and predict OS of KPC mice following DC vaccination.

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.

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.

Hepatocellular carcinoma (HCC) is among the most lethal cancer types despite great advancement in overall survival of the patients over the last decades. Surgical resection or partial hepatectomy has been approved as the curative treatment for early-stage HCC patients however only up to 30% of them are eligible for the procedures. Natural killer (NK) cells are cytotoxic lymphocytes recognized for killing virally infected cells and improving immune functions for defending the body against malignant cells. Although autologous NK cells failed to demonstrate significant clinical benefit, transfer of allogeneic adoptive NK cells arises as a promising approach for the treatment of solid tumors. The immunosuppressive tumor microenvironment and inadequate homing efficiency of NK cells to tumors can inhibit adoptive transfer immunotherapy (ATI) efficacy. However, potential of the NK cells is challenged by the transfection efficiency. The local ablation techniques that employ thermal or chemical energy have been investigated for the destruction of solid tumors for three decades and demonstrated promising benefits for individuals not eligible for surgical resection or partial hepatectomy. Irreversible electroporation (IRE) is one of the most recent minimally invasive ablation methods that destruct the cell within the targeted region through non-thermal energy. IRE destroys the tumor cell membrane by delivering high-frequency electrical energy in short pulses and overcomes tumor immunosuppression. The previous studies demonstrated that IRE can induce immune changes which can facilitate activation of specific immune responses and improve transfection efficiency. In this review paper, we have discussed the mechanism of NK cell immunotherapy and IRE ablation methods for the treatment of HCC patients and the combinatorial benefits of NK cell immunotherapy and IRE ablation.

The purpose of this study was to develop a radiomics signature for distinguishing stage in advanced colon cancer (CC). 195 colon cancer patients were enrolled in this study (stage III, n = 146 vs. stage IV, n = 49) and divided into training cohort (n = 136) and validation cohort (n = 59). A total of 286 radiomic features were extracted from tumor and LN images. A radiomics signature was generated using the least absolute shrinkage and selection operator (LASSO) technique. The relationship between radiomics signature and CC staging was explored using a kernel-based support vector machine (SVM) classifier model. The classification performance was assessed by accuracy and the receiver operating characteristics (ROC) curve. A total of 5 features (2 for tumor and 3 for LN) were selected among 286 features. Radiomics signature built from extracted features successfully differentiated stage III from stage IV CC with no known distant metastases on imaging preoperatively. Furthermore, the SVM classifier model generated using tumor and LN images together achieved better performance than the tumor alone, with accuracies of 86.03% vs. 78.68% and 83.05% vs. 76.27% in training and validation cohorts, respectively. In ROC analysis, the model showed a significant improvement for training (AUC 89.16% vs. 69.5%) and validation cohorts (AUC 75.15% vs. 55%) in comparison with the combined analysis and the tumor alone. In conclusion, the radiomics signature based on preoperative CT may distinguish stage III from stage IV CC with no known distant metastases. In addition, the radiomic features from combined images achieved better classification performance than tumor alone.

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 Kras^LSL-G12D-p53^LSL-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 < .001); tumor ΔADC value positively correlated with tumor fibrosis fraction (R = 0.707, P < .001). IRE induced immunogenic cell death and alleviation of immunosuppressive components in PDAC TME when combined with DC vaccination, including increased tumor infiltration of CD8⁺ T cells and Granzyme B⁺ cells (P = .001, and P = .007, respectively). Our data show that IRE ablation can overcome TME immunosuppression to improve the efficacy of DC vaccination in PDAC. Combination IRE ablation and DC vaccination may enhance therapeutic efficacy for PDAC.

Background

Heterogeneity 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.

Methods

HCC 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.

Results

The 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.

Conclusions

Experimental results indicated that combination therapy significantly enhanced treatment response, resulting in substantial tumor growth reduction in alignment with histological analysis.