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.

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.

Background

To map and quantify the proton exchange rate (k_ex) of brain tissues using improved omega plots in ischemic stroke patients and to investigate whether k_ex can serve as a potential endogenous surrogate imaging biomarker for detecting the metabolic state and the pathologic changes due to ischemic stroke.

New method

Three sets of Z-spectra were acquired from seventeen ischemic stroke patients using a spin echo-echo planar imaging sequence with pre-saturation chemical exchange saturation transfer (CEST) pulse at B₁ of 1.5, 2.5, and 3.5 μT, respectively. Pixel-wise k_ex was calculated from improved omega plot of water direct saturation (DS)-removed Z-spectral signals.

Results

The derived k_ex maps can differentiate infarcts from contralateral normal brain tissues with significantly increased signal (893 ± 52 s^-1vs. 739 ± 34 s^-1, P < 0.001).

Comparison with existing method(s)

The k_ex maps were found to be different from conventional contrasts from diffusion-weighted imaging (DWI), CEST, and semi-solid magnetization transfer (MT) MRI. In brief, k_ex MRI showed larger lesion areas than DWI with different degrees and different lesion contrast compared to CEST and MT.

Conclusions

In this preliminary translational research, the k_ex MRI based on DS-removed omega plots has been demonstrated for in vivo imaging of clinical ischemic stroke patients. As a noninvasive and unique MRI contrast, k_ex MRI at 3 T may serve as a potential surrogate imaging biomarker for the metabolic changes of stroke and help for monitoring the evolution and the treatment of stroke.

Purpose

Z-spectrum imaging, defined as the consecutive collection of images after saturating over a range of frequency offsets, has been recently proposed as a method to measure the fat-water fraction by the simultaneous detection of fat and water resonances. By incorporating a binomial pulse irradiated at each offset before the readout, the spectral selectivity of the sequence can be further amplified, making it possible to monitor the subtle proton resonance frequency shift that follows a change in temperature.

Methods

We tested the hypothesis in aqueous and cream phantoms and in healthy mice, all under thermal challenge. The binomial module consisted of 2 sinc-shaped pulses of opposite phase separated by a delay. Such a delay served to spread out off-resonance spins, with the resulting excitation profile being a periodic function of the delay and the chemical shift.

Results

During heating experiments, the water resonance shifted downfield, and by fitting the curve to a sine function it was possible to quantify the change in temperature. Results from Z-spectrum imaging correlated linearly with data from conventional MRI techniques like T₁ mapping and phase differences from spoiled GRE.

Conclusion

Because the measurement is performed solely on magnitude images, the technique is independent of phase artifacts and is therefore applicable in mixed tissues (e.g., fat). We showed that Z-spectrum imaging can deliver reliable temperature change measurement in both muscular and fatty tissues.

Brown Adipose Tissue (BAT) has a major role in thermoregulation, producing heat by non-shivering thermogenesis. Primarily found in animals and human infants, the presence of significant brown adipose tissue was identified only recently, and its metabolic role in adults was reconsidered. BAT is believed to have an important role in many metabolic diseases, such as obesity and diabetes, and also to be associated with cancer cachexia. Therefore, it is currently a topic of great interest in the research community, and many groups are investigating the mechanisms underlying BAT metabolism in normal and pathological conditions. However, well established non-invasive methods for assessing BAT distribution and function are still lacking. The purpose of this review is to summarize the current state of the art of these methods, with a particular focus on PET, CT and MRI.