Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma.

PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Hemodynamic response during hyperbaric treatment on skeletal muscle in a type 2 diabetes rat model.

Mild hyperbaric treatment prevents type 2 diabetes progression due to increased oxygen concentration and blood flow in skeletal muscle. However, it remains unknown whether this treatment is effective during all stages of type 2 diabetes. This study aimed to investigate the influences of hyperbaric treatment at 1.3 atmospheres absolute (ATA) on hemodynamic response in various stages of type 2 diabetes. Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as models of type 2 diabetes and healthy controls, respectively. Glucose levels were significantly higher in OLETF rats than in LETO rats at all ages. Glucose intolerance gradually increased with age in OLETF rats. Insulin levels in OLETF rats were significantly higher at 20-week-old, however, were significantly lower at 60-week-old than in LETO rats. Oxy-Hb, total Hb, and StO2 in skeletal muscle were increased during hyperbaric treatment in both rats. The hemodynamic changes were significantly higher in OLETF rats than LETO rats, and those changes were also pronounced at 8-week-old compared with other age in OLETF rats. These results suggest that hyperbaric treatment at 1.3 ATA acts on pathophysiological factors and the efficacy could be found only in the early stage of type 2 diabetes.

Effectiveness of daily eccentric contractions induced via kilohertz frequency transcutaneous electrical stimulation on muscle atrophy.

The effects of daily repeated bouts of concentric, isometric, or eccentric contractions induced by high frequency (kilohertz) transcutaneous electrical stimulation in ameliorating atrophy of the soleus muscle in hindlimb unloaded rats were determined. Five groups of male rats were studied: control, hindlimb unloaded for 2 weeks (HU), or HU plus two daily bouts of concentric, isometric, or eccentric high-frequency electrical stimulation-induced contractions of the calf musculature. Soleus mass and fiber size were smaller, the levels of phosphorylated Akt1 and FoxO3a lower, and atrogin-1 and ubiquitinated proteins higher in the HU, and the HU plus concentric or isometric contraction groups than in the control group. In contrast, daily bouts of eccentric contractions maintained these values at near control levels and all measures were significantly different from all other HU groups. These results indicate that daily bouts of eccentric contractions induced by high-frequency stimulation inhibited the ubiquitin-proteasome catabolic pathway and enhanced the Akt1/FoxO3a anabolic pathway that resulted in a prevention of the atrophic response of the soleus muscle to chronic unloading.

Effects of hyperbaric oxygen at 1.25 atmospheres absolute with normal air on macrophage number and infiltration during rat skeletal muscle regeneration.

Use of mild hyperbaric oxygen less than 2 atmospheres absolute (2026.54 hPa) with normal air is emerging as a common complementary treatment for severe muscle injury. Although hyperbaric oxygen at over 2 atmospheres absolute with 100% O2 promotes healing of skeletal muscle injury, it is not clear whether mild hyperbaric oxygen is equally effective. The purpose of the present study was to investigate the impact of hyperbaric oxygen at 1.25 atmospheres absolute (1266.59 hPa) with normal air on muscle regeneration. The tibialis anterior muscle of male Wistar rats was injured by injection of bupivacaine hydrochloride, and rats were randomly assigned to a hyperbaric oxygen experimental group or to a non-hyperbaric oxygen control group. Immediately after the injection, rats were exposed to hyperbaric oxygen, and the treatment was continued for 28 days. The cross-sectional area of centrally nucleated muscle fibers was significantly larger in rats exposed to hyperbaric oxygen than in controls 5 and 7 days after injury. The number of CD68- or CD68- and CD206-positive cells was significantly higher in rats exposed to hyperbaric oxygen than in controls 24 h after injury. Additionally, tumor necrosis factor-α and interleukin-10 mRNA expression levels were significantly higher in rats exposed to hyperbaric oxygen than in controls 24 h after injury. The number of Pax7- and MyoD- or MyoD- and myogenin-positive nuclei per mm2 and the expression levels of these proteins were significantly higher in rats exposed to hyperbaric oxygen than in controls 5 days after injury. These results suggest that mild hyperbaric oxygen promotes skeletal muscle regeneration in the early phase after injury, possibly due to reduced hypoxic conditions leading to accelerated macrophage infiltration and phenotype transition. In conclusion, mild hyperbaric oxygen less than 2 atmospheres absolute with normal air is an appropriate support therapy for severe muscle injuries.

Electrical stimulation using sine waveform prevents unloading-induced muscle atrophy in the deep calf muscles of rat.

The aim of this study was to compare the effects of electrical stimulation by using rectangular and sine waveforms in the prevention of deep muscle atrophy in rat calf muscles. Rats were randomly divided into the following groups: control, hindlimb unloading (HU), and HU plus electrical stimulation (ES). The animals in the ES group were electrically stimulated using rectangular waveform (RS) on the left calves and sine waveform (SS) on the right calves, twice a day, for 2 weeks during unloading. HU for 2 weeks resulted in a loss of the muscle mass, a decrease in the cross-sectional area of the muscle fibers, and overexpression of ubiquitinated proteins in the gastrocnemius and soleus muscles. In contrast, electrical stimulation with RS attenuated the HU-induced reduction in the cross-sectional area of muscle fibers and the increase of ubiquitinated proteins in the gastrocnemius muscle. However, electrical stimulation with RS failed to prevent muscle atrophy in the deep portion of the gastrocnemius and the soleus muscles. Nevertheless, electrical stimulation with SS attenuated the HU-induced muscle atrophy and the up-regulation of ubiquitinated proteins in both gastrocnemius and soleus muscles. This indicates that SS was more effective in the prevention of deep muscle atrophy than RS. Since the skin muscle layers act like the plates of a capacitor, separated by the subcutaneous adipose layer, the SS can pass through this capacitor more easily than the RS. Hence, SS can prevent the progressive loss of muscle fibers in the deep portion of the calf muscles.

Effects of hyperbaric oxygen on metabolic capacity of the skeletal muscle in type 2 diabetic rats with obesity.

We investigated whether hyperbaric oxygen enhances the oxidative metabolic capacity of the skeletal muscle and attenuates adipocyte hypertrophy in type 2 diabetic rats with obesity. Five-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as diabetic animals and nondiabetic controls, respectively, and assigned to control and hyperbaric oxygen groups. Animals in the hyperbaric oxygen group were exposed to an atmospheric pressure of 1.25 with an oxygen concentration of 36% for 3 h daily. The glucose level at 27 weeks of age was significantly higher in OLETF rats than in LETO rats, but the elevation was inhibited in OLETF rats exposed to hyperbaric oxygen. The slow-to-fast fiber transition in the skeletal muscle was observed in OLETF rats, but the shift was inhibited in OLETF rats exposed to hyperbaric oxygen. Additionally, the oxidative enzyme activity of muscle fibers was increased by hyperbaric oxygen. The adipocyte size was larger in OLETF rats than in LETO rats, but hypertrophied adipocytes were not observed in OLETF rats exposed to hyperbaric oxygen. Hyperbaric oxygen enhances glucose and lipid metabolism in the skeletal muscle, indicating that hyperbaric oxygen can prevent elevation of glucose and adipocyte hypertrophy in diabetic rats with obesity.

The combined effect of electrical stimulation and high-load isometric contraction on protein degradation pathways in muscle atrophy induced by hindlimb unloading.

High-load isometric exercise is considered an effective countermeasure against muscle atrophy, but therapeutic electrical stimulation for muscle atrophy is often performed without loading. In the present study, we investigated the combined effectiveness of electrical stimulation and high-load isometric contraction in preventing muscle atrophy induced by hindlimb unloading. Electrical stimulation without loading resulted in slight attenuation of muscle atrophy. Moreover, combining electrical stimulation with high-load isometric contraction enhanced this effect. In electrical stimulation without loading, inhibition of the overexpression of calpain 1, calpain 2, and MuRF-1 mRNA was confirmed. On the other hand, in electrical stimulation with high-load isometric contraction, inhibition of the overexpression of cathepsin L and atrogin-1 mRNA in addition to calpain 1, calpain 2, and MuRF-1 mRNA was confirmed. These findings suggest that the combination of electrical stimulation and high-load isometric contraction is effective as a countermeasure against muscle atrophy.

The combined effect of electrical stimulation and resistance isometric contraction on muscle atrophy in rat tibialis anterior muscle.

Electrical stimulation has been used to prevent muscle atrophy, but this method is different in many previous studies, appropriate stimulation protocol is still not decided. Although resistance exercise has also been shown to be an effective countermeasure on muscle atrophy, almost previous studies carried out an electrical stimulation without resistance. It was hypothesized that electrical stimulation without resistance is insufficient to contract skeletal muscle forcefully, and the combination of electrical stimulation and forceful resistance contraction is more effective than electrical stimulation without resistance to attenuate muscle atrophy. This study investigated the combined effects of electrical stimulation and resistance isometric contraction on muscle atrophy in the rat tibialis anterior muscle. The animals were divided into control, hindlimb unloading (HU), hindlimb unloading plus electrical stimulation (ES), and hindlimb unloading plus the combination of electrical stimulation and resistance isometric contraction (ES+IC). Electrical stimulation was applied to the tibialis anterior muscle percutaneously for total 240 sec per day. In the ES+IC group, the ankle joint was fixed to produce resistance isometric contraction during electrical stimulation. After 7 days, the cross-sectional areas of each muscle fiber type in the HU group decreased. Those were prevented in the ES+IC group rather than the ES group. The expression of heat shock protein 72 was enhanced in the ES and ES+IC groups. These results indicated that although electrical stimulation is effective to prevent muscle atrophy, the combination of electrical stimulation and isometric contraction have further effect.