Vascular Normalization Caused by Short-Term Lenvatinib Could Enhance Transarterial Chemoembolization in Hepatocellular Carcinoma.

We describe the clinical effects of short-term lenvatinib administration prior to conventional transarterial chemoembolization (cTACE) on tumor vasculature. Two patients with unresectable hepatocellular carcinoma underwent high-resolution digital subtraction angiography (DSA) and perfusion four-dimensional computed tomography during hepatic arteriography (4D-CTHA) before and after administration of lenvatinib treatment. The doses and periods of lenvatinib administration were, respectively, 12 mg/day for 7 days and 8 mg/day for 4 days. In both cases, high-resolution DSA revealed a decrease in dilatation and tortuosity of the tumor vessels. Furthermore, the tumor staining became more refined, and newly formed tiny tumor vessels were observed. Perfusion 4D-CTHA revealed a decrease in arterial blood flow to the tumor by 28.6% (from 487.9 to 139.5 mL/min/100 mg) and 42.5% (from 288.2 to 122.6 mL/min/100 mg) in the two cases, respectively. The cTACE procedure resulted in good lipiodol accumulation and complete response. Patients have remained recurrence-free for 12 and 11 months after the cTACE procedure, respectively. The administration of short-term lenvatinib in these two cases resulted in the normalization of tumor vessels, which likely led to improved lipiodol accumulation and a favorable antitumor effect.

Drug Release Property of Lipiodol Emulsion Formed by Glass Membrane Emulsification Device for Transarterial Chemoembolization.

PURPOSE: To evaluate physiochemical characteristics of emulsions formed by a modified emulsification device and to compare in vitro drug release properties of ethiodized oil (Lipiodol)-drug solution emulsion formed by the device and a 3-way-stopcock for conventional transarterial chemoembolization. MATERIALS AND METHODS: A V-shaped pumping emulsification device with a 100-µm-micropore glass membrane was developed to reduce the resistance of pumping. Epirubicin solution was mixed with Lipiodol (ratio 1:2) with pumping exchanges through the device. The percentage of water-in-oil (W/O) and droplet size distribution and viscosity were evaluated. The in vitro drug release properties were compared between using the device and a 3-way-stopcock. RESULTS: Percentage of W/O was 98.45 ± 0.03%. The median droplet size was 22.58 ± 1.70 µm, and the viscosity was 143.70 ± 12.36 cP. The released epirubicin at 0 min was 1.73 ± 1.05% in the device, whereas 41.02 ± 7.27% in a 3-way-stopcock (P < 0.001). The half-life of release (t50%) of the device was significantly longer than that of a 3-way-stopcock (175 ± 25 vs. 8 ± 6 min, P < 0.001). CONCLUSION: The V-shaped emulsification device with a 100-µm-micropore glass membrane can form nearly 100% W/O emulsion with homogenous droplet sizes. Emulsion formed by the device showed a slower epirubicin release property compared with that of a 3-way-stopcock.

Improved Local Tumor Control and Survival Rates by Obtaining a 3D-Safety Margin in Superselective Transarterial Chemoembolization for Small Hepatocellular Carcinoma.

OBJECTIVE: To investigate technical factors affecting local tumor control of small hepatocellular carcinoma (HCC) treated by superselective conventional transarterial chemoembolization (cTACE) using lipiodol and to compare prognoses between groups with and without these factors. MATERIALS AND METHODS: Sixty-three consecutive patients with 73 HCC nodules (diameter, 1-3 cm) treated by cTACE were retrospectively analyzed. A positive or a negative 3D-safety margin was defined as a ≥ 1-mm area of lipiodol accumulation or as a diameter of lipiodol accumulation < 1 mm in liver parenchyma surrounding the tumor using plain CT images obtained within a week after TACE. Uni- and multivariate analyses were performed to identify technical factors determining local tumor control rate. Subgroup analysis of survival rates in treatment-naïve patients was performed according to the detected factors. RESULTS: In univariate analyses, three-dimensional (3D)-safety margin and portal vein visualization were associated with local tumor control rates. In multivariate analysis, only positive 3D-safety margin remained a significant contributor (p = 0.001). Two-year cumulative local disease-free survival rates with positive and negative 3D-safety margin were 82.8% and 19.3%, respectively (p = 0.001). In subgroup survival analysis of the 36 newly diagnosed patients, the 1-, 2-, 3-, 4-, and 5-year cumulative OS rates for patients with and without positive margins were 100% versus 100%, 96.4% versus 75.0%, 81.8% versus 62.5%, 74.4% versus 41.7%, and 47.0% versus 0%, respectively (median survival time; 57.6 months vs. 37.1, p = 0.047). CONCLUSION: Obtaining a 3D-safety margin can suppress local tumor recurrence and prolong survival in superselective cTACE for small HCC.

FF-10832 enables long survival via effective gemcitabine accumulation in a lethal murine peritoneal dissemination model.

Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.

Coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone improves postprandial endothelial dysfunction in patients with borderline and stage 1 hypertension.

PURPOSE: The purpose of this study was to evaluate acute effects of coffee with a high content of chlorogenic acids and different hydroxyhydroquinone contents on postprandial endothelial dysfunction. METHODS: This was a single-blind, randomized, placebo-controlled, crossover-within-subject clinical trial. A total of 37 patients with borderline or stage 1 hypertension were randomized to two study groups. The participants consumed a test meal with a single intake of the test coffee. Subjects in the Study 1 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or coffee with a high content of chlorogenic acids and a high content of hydroxyhydroquinone with crossover. Subjects in the Study 2 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or placebo coffee with crossover. Endothelial function assessed by flow-mediated vasodilation and plasma concentration of 8-isoprostanes were measured at baseline and at 1 and 2 h after coffee intake. RESULTS: Compared with baseline values, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, significantly improved postprandial flow-mediated vasodilation and decreased circulating 8-isoprostane levels. CONCLUSIONS: These findings suggest that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is effective for improving postprandial endothelial dysfunction. CLINICAL TRIAL REGISTRATION: URL for Clinical Trial: https://upload.umin.ac.jp ; Registration Number for Clinical Trial: UMIN000013283.

Relationship between aortic mineral elements and osteodystrophy in mice with chronic kidney disease.

In chronic kidney disease (CKD), osteodystrophy and arterial calcification often coexist. However, arterial alterations have not been addressed in CKD unaccompanied by evidence of calcification. We investigated the association of phosphate (P) and calcium (Ca) accumulation in calcification-free aortas with CKD-induced osteodystrophy. Aortic accumulation of magnesium (Mg), an inhibitor of calcification, was also examined. Male mice aged 26 weeks with CKD characterized by hyperparathyroidism and hyperphosphatemia (Nx, n = 8) and age-matched healthy male mice (shams, n = 8) were sampled for blood, and thoracic vertebrae and aortas were harvested. Bone structure and chemicals were analyzed by microcomputed tomography and infrared microspectroscopy, respectively, and aortic accumulation of P, Ca, and Mg was evaluated by plasma-atomic emission spectrometry. Volume fractions of cortical and trabecular bones were smaller in Nx than in sham animals (P < 0.05), attributed to cortical thinning and reduction in trabecular number, respectively. Bone chemicals were not different between the groups. No calcification was found in either group, but P, Ca, and Mg contents were higher in Nx than in shams (P < 0.05). The mass ratio of Ca/P was lower in Nx than in shams (P < 0.05), but that of Mg/Ca and Mg/P was not different between the groups. Aortic P and Ca contents were inversely correlated with the volume fraction of cortical bone (P < 0.05). In conclusion, the relationship of osteodystrophy with aortic P and Ca accumulation suggests the existence of a bone-vascular axis, even in calcification-free arteries in CKD. The preservation of ratios of Mg/Ca and Mg/P despite CKD development might contribute to calcification resistance.

Effects of vitamin K on the morphometric and material properties of bone in the tibiae of growing rats.

Suboptimal vitamin K nutriture is evident during rapid growth. We aimed to determine whether vitamin K(2) (menaquinone-4 [MK-4]) supplementation is beneficial to bone structure and intrinsic bone tissue properties in growing rats. Male Wistar rats (5 weeks old) were assigned to either a control diet (n = 8) or an MK-4-supplemented diet (22 mg d(-1) kg(-1) body weight, n = 8). After a 9-week feeding period, we determined the serum concentration ratio of undercarboxylated osteocalcin to γ-carboxylated osteocalcin and the urinary deoxypyridinoline level. All rats were then euthanized, and their tibiae were analyzed by micro-computed tomography for trabecular architecture and synchrotron radiation micro-computed tomography for cortical pore structure and mineralization. Fourier transform infrared microspectroscopy and a nanoindentation test were performed on the cortical midlayers of the anterior and posterior cortices to assess bone tissue properties. Neither body weight nor tibia length differed significantly between the 2 groups. Dietary MK-4 supplementation decreased the ratio of undercarboxylated osteocalcin to γ-carboxylated osteocalcin but did not affect deoxypyridinoline, indicating a positive effect on bone formation but not bone resorption. Trabecular volume fraction and thickness were increased by MK-4 (P < .05). Neither the cortical pore structure nor mineralization was affected by MK-4. On the other hand, MK-4 increased mineral crystallinity, collagen maturity, and hardness in both the anterior and posterior cortices (P < .05). These data indicate the potential benefit of MK-4 supplementation during growth in terms of enhancing bone quality.

Insect antifeedants from tropical plants II: structure of zumsin.

A novel A-seco limonoid was isolated from methanolic extract of Croton jatrophoides and designated as zumsin. This compound showed potent antifeedant activity against two lepidopteran larvae, pink bollworm, Pectinophora gossypiella (PC(50) = 1 microg/cm(2), PC(95) = 8 microg/cm(2)), and fall armyworm, Spodoptera frugiperda (PC(50) = 2 microg/cm(2), PC(95) = 16 microg/cm(2)). The structure of zumsin was determined as 1 using a variety of spectroscopic methods including nuclear magnetic resonance, mass spectrometry, and circular dichroism. The structure consists of an A'-B trans-fused ring while dumsin (2), a constituent of the same source, maintains an A'-B cis-fused ring, and suggests two unique biosynthetic processes after A ring oxidative expansion.

Cardioprotective effects of 9-hydroxyellipticine on ischemia and reperfusion in isolated rat heart.

We determined the effect of 9-hydroxyellipticine (9HE) on ryanodine receptor (RyR) and cardiac function after global ischemia in isolated rat hearts. The binding of [3H]-ryanodine in rabbit cardiac sarcoplasmic reticulum was displaced by 9HE in a biphasic manner corresponding to the two sites model with IC50 values of 6.1 microM and 55 mM. The increase of the intracellular Ca2+ concentration induced by caffeine in CHO cells expressing cardiac-type RyR was suppressed by 9HE in a concentration-dependent manner. Pretreatment of the heart with 9HE decreased the total duration of reperfusion-induced ventricular fibrillation (VF) and delayed the onset of VF. There was also a significant recovery of contractile force of ischemic hearts following 9HE. Unlike nifedipine, an L-type Ca2+-channel blocker, 9HE did not suppress the contraction of rat papillary muscles. Thus, 9HE exerts the cardioprotective effects against ischemia /reperfusion injury without changing hemodynamic indices.