The Current Role of Stereotactic Body Radiation Therapy (SBRT) in Hepatocellular Carcinoma (HCC)

The role of stereotactic body radiotherapy (SBRT), which can deliver high radiation doses to focal tumors, has greatly increased in not only early-stage hepatocellular carcinoma (HCC), but also in portal vein or inferior vena cava thrombi, thus expanding this therapy to pre-transplantation and the treatment of oligometastases from HCC in combination with immune checkpoint inhibitors (ICI). In early-stage HCC, many promising prospective results of SBRT have been reported, although SBRT is not usually indicated as a first treatment potion in localized HCC according to several guidelines. In the treatment of portal vein or inferior vena cava tumor thrombi, several reports using various dose-fraction schedules have shown relatively good response rates with low toxicities and improved survival due to the rapid advancements in systemic therapy. Although SBRT is regarded as a substitute therapy when conventional bridging therapies to transplantation, such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), are not applicable or fail in controlling tumors, SBRT may offer advantages in patients with borderline liver function who may not tolerate TACE or RFA, according to several reports. For oligometastases, the combination of SBRT with ICI could potentially induce an abscopal effect in patients with HCC, which is expected to provide the rationale for SBRT in the treatment of oligometastatic disease in the near future

Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats

<div><p>Gamma-aminobutyric acid (GABA) has been shown to induce excitation on immature neurons due to increased expression of Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), and the transition of GABAergic signaling from excitatory to inhibitory occurs before birth in the rat spinal cord and spreads rostrally according to the developmental changes in cation-chloride co-transporter expression. We previously showed that midazolam activates the hippocampal CA3 area and induces less sedation in neonatal rats compared with adolescent rats in an NKCC1-dependent manner. In the present study, we tested the hypothesis that propofol-induced loss of righting reflex (LORR) but not immobilizing actions are modulated by NKCC1-dependent mechanisms and reduced in neonatal rats compared with adolescent rats. We estimated neuronal activity in the cortex, hippocampus and thalamus after propofol administration with or without bumetanide, an NKCC1 inhibitor, by immunostaining of phosphorylated cyclic adenosine monophosphate-response element binding protein (pCREB). We studied effects of bumetanide on propofol-induced LORR and immobilizing actions in postnatal day 7 and 28 (P7 and P28) rats. The pCREB expression in the cortex (P = 0.001) and hippocampus (P = 0.01) was significantly greater in the rats receiving propofol only than in the rats receiving propofol plus bumetanide at P 7. Propofol-induced LORR or immobilizing effects did not differ significantly between P7 and P28. Bumetanide significantly enhanced propofol-induced LORR (P = 0.031) but not immobilization in P7 rats. These results are partially consistent with our hypothesis. They suggest that propofol may activate the rostral but not caudal central nervous system dependently on NKCC1, and these differential actions may underlie the different properties of sedative and immobilizing actions observed in neonatal rats.</p></div

Changes in the expression of phosphorylated cyclic adenosine monophosphate-response element-binding protein (pCREB) after intraperitoneal administration of propofol in postnatal day 7 rats.

<p>A, B and C (upper panels: ×4 magnification; lower panels: ×8 magnification) are photomicrographs of pCREB immunostaining in the cortex (retrosplenial granular cortex and retrosplenial granular b cortex) of rats. D, E and F (upper panels: ×4 magnification; lower panels: ×8 magnification) are those of pCREB immunostaining in the hippocampal CA3 area. G, H and I (upper panels: ×4 magnification; lower panels: ×8 magnification) are those of pCREB immunostaining in the thalamus. Graphs in J, K and L show the number of pCREB-positive cells in the cortex, hippocampus and thalamus, respectively. Data are given as mean and SD. *P = 0.01, ***P = 0.001 and ****P<0.001, respectively. Data are derived from 4 slices in each group.</p

Durations of Loss of Righting Reflex in the Saline + Propofol and Bumetanide + Propofol Groups in P7 and P28 Rats.

<p>Durations of Loss of Righting Reflex in the Saline + Propofol and Bumetanide + Propofol Groups in P7 and P28 Rats.</p

Changes in the expression of phosphorylated cyclic adenosine monophosphate-response element-binding protein (pCREB) after intraperitoneal administration of propofol in postnatal day 28 rats.

<p>A, B and C (upper panels: ×4 magnification; lower panels: ×8 magnification) are photomicrographs of pCREB immunostaining in the cortex (retrosplenial granular cortex and retrosplenial granular b cortex) of rats. D, E and F (upper panels: ×4 magnification; lower panels: ×8 magnification) are those of pCREB immunostaining in the hippocampal CA3 area. G, H and I (upper panels: ×4 magnification; lower panels: ×8 magnification) are those of pCREB immunostaining in the thalamus. Graphs in J, K and L show the number of pCREB-positive cells in the cortex, hippocampus and thalamus, respectively. Data are given as mean and SD. **P<0.01 and ***P = 0.001, respectively. Data are derived from 4 slices in each group.</p