A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors.

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).

Thyroid lobe size predicts risk of postoperative temporary recurrent laryngeal nerve paralysis.

OBJECTIVES: In patients who had undergone thyroidectomy in Japan for benign tumor, we determined whether thyroid lobe size correlates with temporary recurrent laryngeal nerve paralysis (T-RLNP). METHODS: We retrospectively collected medical record data on usage of intraoperative neuromonitoring, laterality of thyroidectomy, amount of bleeding during surgery, duration of surgery, and whether the surgeon was a board certified otorhinolaryngologist as determined by the Oto-Rhino-Laryngological Society of Japan. Thyroid size was measured in preoperative axial computed tomography (CT) images. Receiver operating characteristic (ROC) curve analysis was used to determine the thyroid size that predicted a high risk of T-RLNP or permanent recurrent laryngeal nerve paralysis (P-RLNP). RESULTS: Of the 146 eligible patients identified, 9 (6.2%) developed T-RLNP and 2 (1.4%) developed P-RLNP. The amount of bleeding during thyroidectomy was significantly greater in T-RLNP patients than in P-RLNP patients. Thyroid sizes in CT images were significantly larger in T-RLNP patients compared to patients who did not develop RLNP (referred to hereafter as N-RLNP). ROC analysis revealed that 1.3% of thyroid lobes with an area of less than 1000.0 mm2, and 9.9% of thyroid lobes with an area of greater than 1000.0 mm2 were at risk for T-RLNP. CONCLUSION: We presented evidence that thyroid sizes, as measured on preoperative axial CT images, were larger in T-RLNP patients than in N-RLNP patients. Our results indicate a connection between benign thyroid tumor stretch injuries and T-RLNP. LEVEL OF EVIDENCE: IV.

Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation.

BACKGROUND: A high intake of fructose increases the risk for hyperuricemia. It has been reported that long-term fructose consumption suppressed renal uric acid excretion and increased serum uric acid level. However, the effect of single administration of fructose on excretion of uric acid has not been clarified. METHODS: We used male Wistar rats, which were orally administered fructose (5g/kg). Those rats were used in each experiment at 12h after administration. RESULTS: Single administration of fructose suppressed the function of ileal uric acid excretion and had no effect on the function of renal uric acid excretion. Breast cancer resistance protein (BCRP) predominantly contributes to intestinal excretion of uric acid as an active homodimer. Single administration of fructose decreased BCRP homodimer level in the ileum. Moreover, diphenyleneiodonium (DPI), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), recovered the suppression of the function of ileal uric acid excretion and the Bcrp homodimer level in the ileum of rats that received single administration of fructose. CONCLUSIONS: Single administration of fructose decreases in BCRP homodimer level, resulting in the suppression the function of ileal uric acid excretion. The suppression of the function of ileal uric acid excretion by single administration of fructose is caused by the activation of Nox. The results of our study provide a new insight into the mechanism of fructose-induced hyperuricemia.

Giant Cell Tumor of the Skull: Review of the Literature.

BACKGROUND: Giant cell tumors (GCTs) are rare in the skull. The present report describes a case with a primary GCT located in the temporal bone and reviews the relevant literature. We also propose a treatment strategy for GCT of the skull. CLINICAL PRESENTATION: A 41-year-old man presented with headache and auditory disturbance. Radiologic images showed a lytic expansive extradural lesion originating primarily from the right temporal bone and expanding into the middle cranial fossa and the infratemporal fossa. A biopsy specimen of the lesion was obtained from the external auditory meatus. Total removal was performed with temporal craniectomy, mandibular condylar process removal, tympanoplasty, and mastoidectomy. DISCUSSION: The rate of recurrence of GCTs is related to complete resection and location of the GCT rather than to the degree of invasiveness. Some of the mononuclear cells and stromal cells in GCT express receptor activator of nuclear factor κ-ß ligand (RANKL). Because inhibition of RANKL and bisphosphonate therapy might eliminate giant cells, this approach might be useful for recurrent or unresectable GCTs of the skull. CONCLUSIONS: Preoperative diagnosis by biopsy is important in determining the therapeutic strategy of GCTs. Complete resection is important to reduce the recurrence rate of GCTs in the skull.

Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin--Insights From the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: In 21,105 patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial, edoxaban was non-inferior to warfarin in preventing thromboembolic events while reducing bleeding. We compared results in Japan with the rest of East Asia (EA), including China, Korea, and Taiwan. METHODS AND RESULTS: We compared baseline characteristics, time-in-therapeutic range (TTR) for warfarin, and outcomes (efficacy: stroke or systemic embolic events [SEE], safety: major bleeding). Interaction P values were used to assess for effect modification of treatment (higher-dose edoxaban [HDE, 60 mg/30 mg] vs. warfarin; lower-dose edoxaban [LDE, 30 mg/15 mg] vs. warfarin) by region with adjustments for baseline characteristics. Fewer patients in Japan (n=1,010) were female, taking aspirin or amiodarone, naïve to warfarin (P<0.001 for each), had a history of stroke or transient ischemic attack (P=0.02), and more patients needed dose reduction (P<0.001) compared with EA (n=933). The mean TTR was higher in Japan (70% vs. 56%, P<0.001). Evidence for statistical interactions was observed for HDE vs. warfarin by region for stroke/SEE (adjusted P-int=0.052) and major bleeding (adjusted P-int=0.048) with greater relative efficacy and safety with HDE in EA compared with Japan. No interactions were observed for LDE vs. warfarin after adjustment. CONCLUSIONS: HDE had a greater relative efficacy and safety in EA compared with Japan that was only partially explained by differences in baseline characteristics and TTR.

Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen.

The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging.

Intestinal P-glycoprotein expression is multimodally regulated by intestinal ischemia-reperfusion.

PURPOSE: Reactive oxygen species (ROS) have multiple physiological effects that are amount-dependent. ROS are one of the causes of intestinal ischemia-reperfusion (I/R) injury. In this study, we investigated whether the amount of ROS and the degree of intestinal I/R injury affect the expression level of P-glycoprotein (P-gp). METHODS: . We used hydrogen peroxide (H2O2) as ROS in in vitro experiments. Intestinal I/R model rats, which were subjected 15-min ischemia (I/R-15), were used in in vivo experiments. RESULTS: P-gp expression in Caco-2 cells was increased in response to 1 µM of H2O2 but decreased upon exposure to 10 mM of H2O2. We previously reported that P-gp expression is decreased after intestinal I/R with 30-min ischemia (I/R-30), which time a large amount of ROS is generated. I/R-15 induced slightly less mucosal and oxidative injury than did I/R-30. P-gp expression in the jejunum was increased at 1 h after I/R-15, and ileal paracellular permeability was increased. The blood concentration of tacrolimus, a P-gp substrate, was lower during 0-20 min but was higher during 40-90 min post-administration compared with that in the sham-operated rats. P-gp expression in the ileum was decreased at 6 h after I/R-15, due to abnormal localization of P-gp, resulting in a high blood tacrolimus concentration in rats reperfused for 6 h. CONCLUSIONS: ROS multimodally regulate P-gp expression depending on its amount. This is important for understanding the pattern of P-gp expression after intestinal I/R.

Improvement of uniformity of the negative ion beams by tent-shaped magnetic field in the JT-60 negative ion source.

Non-uniformity of the negative ion beams in the JT-60 negative ion source with the world-largest ion extraction area was improved by modifying the magnetic filter in the source from the plasma grid (PG) filter to a tent-shaped filter. The magnetic design via electron trajectory calculation showed that the tent-shaped filter was expected to suppress the localization of the primary electrons emitted from the filaments and created uniform plasma with positive ions and atoms of the parent particles for the negative ions. By modifying the magnetic filter to the tent-shaped filter, the uniformity defined as the deviation from the averaged beam intensity was reduced from 14% of the PG filter to ∼10% without a reduction of the negative ion production.

Quercetin-3-rhamnoglucoside (rutin) stimulates transport of organic anion compounds mediated by organic anion transporting polypeptide 2B1.

Quercetin-3-rhamnoglucoside (rutin) has a wide spectrum of biochemical and pharmacological activities. Rutin is absorbed mainly in its unmetabolized form. Organic anion transporting polypeptide (OATP) 2B1 is a major uptake transporter in the intestine. Thus, it is important for the prevention of adverse events to understand drug interactions mediated by OATP2B1 in the absorption process. This study assessed the effect of rutin on transport by OATP2B1. Rutin stimulated the uptake of estrone-3-sulfate (E-3-S), taurocholic acid (TCA), cholic acid (CA) and rosuvastatin by OATP2B1, but not p-coumaric acid or ferulic acid. The EC50 of rutin for transport by OATP2B1 was 2.32 µm. The Km value of E-3-S for OATP2B1 in the presence of rutin (9.21 µm) was almost the same as that in the absence of rutin (8.53 µm). On the other hand, the Vmax of E-3-S transport by OATP2B1 in the presence of rutin (270 pmol/mg protein/min) was 1.2-fold higher than that in the absence of rutin (218 pmol/mg protein/min). Moreover, the expression level of OATP2B1 on the cell membrane was increased by treatment with rutin for 5 min without alteration of the total OATP2B1 expression level. Moreover, the increase in the localization of OATP2B1 at the cell surface was detected by the immunocytochemistry. The stimulatory effect of rutin is a little weak but may affect the absorption of OATP2B1 substrates, because rutin is taken daily in foods and its intestinal concentration would reach the stimulatory range of OATP2B1.

Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver.

Reactive oxygen species (ROS) have physiological function and involve alteration of physical state. However, it is not clear effect of oxidative stress on pharmacokinetics. Organic anion transporting polypeptides (human: OATPs, rodent: Oatps) are important for uptake of endogenous and exogenous compounds into hepatocytes. Thus, alteration of OATPs/Oatps expression level may affect pharmacokinetics of various drugs. In this study, we investigated the alteration of OATPs/Oatps expression levels and function by oxidative stress, and the effect of alteration of those on pharmacokinetics of a typical OATPs/Oatps substrate pravastatin. OATPs/Oatps expression levels and function were altered by H2O2-induced oxidative stress in in vitro experiments. The alteration of Oatps expression by oxidative stress also occurred in in vivo experiments. Oatp1a1, Oatp1a4 and Oatp1b2 expression in the liver were decreased in rats fed powdery diet containing 2% inosine, which induces oxidative stress through activation of xanthine oxidase, for 1 day. The decrease in Oatps expression levels by oxidative stress caused the suppression of pravastatin uptake to the liver, and resulted in high plasma concentration of pravastatin and low biliary excretion. In conclusion, oxidative stress induces alteration of OATPs/Oatps expression and function in hepatocytes, resulting in alteration of pharmacokinetics of their substrates.

Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis.

AIM: Non-alcoholic steatohepatitis (NASH) is one of the representative liver diseases in developed countries. Diagnosis of NASH is dependent on histological findings from liver biopsy. METHODS: The usefulness of contrast ultrasound with Levovist for diagnosis of NASH is described. 2.5 g of ultrasound contrast agent Levovist was injected intravenously. The liver was scanned at 5, 10, 15, 20, 30, 40 and 50 min and changes in microbubble accumulation were evaluated. The signal intensity from regions of interest (ROI) on the contrast images was measured and estimated using time intensity curves (TICs). Twenty-one patients with NASH, 33 with non-alcoholic fatty liver disease (NAFLD) and 10 healthy volunteers (HV) were studied. The signal intensity was measured quantitatively at 5 and 20 min after injection. RESULTS: There was a statistically significant decrease in NASH, when compared with NAFLD and HV groups. These changes in signal intensity were not correlated to the degree of fibrosis and steatosis in histological study. The sensitivity, specificity and overall accuracy obtained from the receiver operating characteristic (ROC) curve were 100% when the cut-off value was set at 43.6 of signal intensity at 20 min. CONCLUSION: The Levovist contrast study is a useful screening examination which picks up NASH among fatty liver patients.

Dynamic US contrast study of the liver: Vascular and delayed parenchymal phase.

We evaluated the time-intensity curves of the ultrasound contrast agent, Levovist, in the aorta, portal vein and liver parenchyma in order to define distribution of the agent when it is administered by an intravenous bolus injection. Twelve healthy volunteers were studied. All 12 subjects were examined for the study of vascular phase and five of the subjects were examined for the study of delayed parenchymal phase. To evaluate vascular enhancement, transverse abdominal scanning was performed. To evaluate parenchymal enhancement, liver scanning was done just once at 14 time points up to 60 min after injection. The time-intensity curves in the aorta and the portal vein indicated the conventional curves of blood pool agents such as iodine CT agents and gadolinium MRI agents. They showed steep initial rises and peaks at 20 s and 30 s after injection, respectively. Parenchymal enhancement reached a peak five minutes after injection, with a plateau for 20 min subsequently. It has been proved that there are two phases of Levovist contrast ultrasonography, the vascular phase and the delayed parenchymal phase.

Differential diagnosis of hepatic nodules using delayed parenchymal phase imaging of levovist contrast ultrasound: comparative study with SPIO-MRI.

T2-weighted fast spin echo images and T2*-weighted gradient-echo images of superparamagnetic iron oxide magnetic resonance imaging (SPIO-MRI) have been reported to reflect the number and function of macrophages in reticuloendothelial organs and be useful to differentiate malignant tumors from benign nodules of liver. We tried to prove that contrast-enhanced ultrasound can diagnose hepatocellular carcinoma (HCC) by comparing the findings of SPIO-MRI and the findings of the liver parenchyma on the delayed parenchymal phase of ultrasound imaging using the intravenous contrast agent Levovist, not through the evaluation of vascular imaging. Forty-six patients (52 nodules) with histopathological diagnosis of hepatic tumors were studied. They consisted of 11 non-malignant nodules (six regenerative nodules and five dysplastic nodules) and 41 HCC. All the patients were examined by Levovist contrast-enhanced ultrasonography and SPIO-MRI. The delayed liver parenchymal images of contrast-enhanced ultrasound using the intravenous contrast agent Levovist were similar to those observed on SPIO-MRI. The similarity of both findings suggests that delayed phase imaging by Levovist is closely related to the number and function of Kupffer cells in liver tumors. The diagnostic accuracy of contrast-enhanced ultrasound for HCC was high (90.4%) demonstrating that it is as reliable as SPIO-MRI.