Pharmacokinetic study of lenvatinib in Chinese patients with solid tumors.

Aim: To assess the pharmacokinetics of once-daily oral lenvatinib 24 mg in Chinese patients. Material & methods: Patients had any solid tumor (except hepatocellular carcinoma) that was resistant to standard antitumor therapies or for which no appropriate treatment was available. Results: Twelve patients were enrolled. Maximum plasma concentrations of lenvatinib were observed at 2 and 4 h (median) after single and multiple doses (day 15), respectively. Steady state was achieved within 8 days. The geometric mean maximum observed concentration at steady state was 258 ng/ml (coefficient of variance: 49.2%); and the geometric mean area under the concentration-time curve from zero to 24 h at steady state was 3090 ng•h/ml (coefficient of variance: 44.7%). No accumulation was seen after 15 days. Conclusion: Lenvatinib pharmacokinetic data in Chinese patients are consistent with data in multinational trials, supporting usage of the 24-mg dose. Clinical trial registration: NCT03009292 (ClinicalTrials.gov).

"Nonsignificant" early repolarization pattern on postresuscitation ECG as a harbinger of impending electrical storm.

We report a 55-year-old man who was resuscitated from out-of-hospital cardiac arrest and subsequently developed three episodes of ventricular fibrillation (VF) on the same day. Early repolarization (ER) pattern was not significant (<0.1 mV) on postresuscitation ECG. However, ER pattern became evident (0.25 mV) before the onset of VF and then completely disappeared. The unusual dynamics of ER pattern observed in the present case could be called "masked" ER syndrome.

Relationship between electrical conduction and phasic left atrial function: P-wave signal-averaged electrocardiography and time-left atrial volume curve assessments using two-dimensional speckle-tracking echocardiography.

P-wave signal-averaged electrocardiography (P-SAECG) can detect imperceptible conduction abnormalities, and volume analysis using two-dimensional speckle-tracking echocardiography (2-DSTE) allows us to easily measure the phasic function of the left atrium (LA). Both conduction abnormalities and functional deformation of the LA may be linked to the clinical outcome; however, the exact relationship is unclear. The aim of this study was to investigate the relationship between the phasic function of the LA and electrical conduction using P-SAECG and 2-DSTE. The subjects were 112 male volunteers (age 46.9 ± 13.2 years) with normal cardiac function who underwent P-SAECG and 2-DSTE. The filtered p-wave duration (FPD) and the root-mean-square voltage for the last 20 ms (RMS20) on P-SAECG wave were measured in ms and µV, respectively. Total emptying function (EF) (reservoir function), passive EF (conduit function), and active EF (booster pump function) of the LA were calculated as percentages to evaluate phasic LA function using 2DSTE. The mean FPD was 134.3 ± 11.7 ms and the mean RMS20 was 4.59 ± 2.39 µV. The mean total EF was 60.5 ± 13.1%, mean passive EF was 39.4 ± 13.9%, and mean active EF was 35.1 ± 13.9%. FPD had a negative correlation with passive EF (r = - 0.20, p = 0.039). FPD showed no significant relationship with total EF (r = - 0.03, p = 0.78) or active EF (r = 0.13, p = 0.18). There was a significant association between RMS20 and passive EF (r = 0.19, p = 0.048); however, no there was no correlation between RMS20 and total EF (r = 0.12, p = 0.23), or between RMS20 and passive EF (r = - 0.02, p = 0.86). In multivariate regression analysis, passive EF was an independent factor that influenced FPD duration. This study indicated that FPD was associated with conduit function, which includes phasic LA function. Therefore, electrical conduction of the LA and left ventricular diastolic function are closely related. In the clinical setting, when conduction abnormalities are detected, lifestyle measures or interventions can be applied to reduce cardiovascular risk.

Shift in the retrograde atrial activation sequence after radiofrequency catheter ablation in left variant atypical atrioventricular nodal reentrant tachycardia.

The role of left AV nodal (SVN) connections in the genesis of "left-variant" atypical atrioventricular nodal reentrant tachycardia (AVNRT) and those with multiple retrograde pathways remain unclear. We describe an unusual case of "left-variant" atypical AVNRT, where change in the retrograde earliest atrial activation site (REAAS) at the coronary sinus (CS) following radiofrequency catheter ablation (RFCA) was observed. Our observation suggests that the REAAS, that is, the left AVN connections, could participate in the formation of the reentrant circuit of "left-variant" atypical AVNRT. Furthermore, its atrial breakthroughs involved as a circuit of SVT could be (functionally) multiple.

Unusual manifestation of left ventricular electrical conduction delay on the surface 12-lead electrocardiogram in a patient with prior myocardial infarction.

We describe a 41-year-old man with a prior history of myocardial infarction, whose surface 12-lead electrocardiogram did not show typical left bundle-branch block pattern or wide QRS complex. However, electrophysiological study showed distinct left ventricular electrical conduction delays. The surface 12-lead electrocardiogram modified to the paper at 50 mm/s and double standard (20 mm equals 1 mV) revealed obvious notches of the terminal forces of the QRS in leads II, III, aVL, aVF, V3, V4, V5, and V6, these might be partially consistent with left ventricular electrical conduction delay in the scar lesion of the infero-posterior of the ventricle.

Microvolt T-wave alternans monitoring in a patient with levofloxacin-induced Torsade de Pointes.

We present the case of a 62-year-old woman with levofloxacin-induced Torsade de Pointes, in whom microvolt T-wave alternans was measured during acute hospitalization and when QT interval was dynamically changing, illustrating a means for monitoring proarrhythmia.

Design and daytime performance of laser-induced fluorescence spectrum lidar for simultaneous detection of multiple components, dissolved organic matter, phycocyanin, and chlorophyll in river water.

In this work, we developed mobile laser-induced fluorescence spectrum (LIFS) lidar based on preliminary experiments on the excitation emission matrix of a water sample and a method for reducing solar background light using the synchronous detection technique. The combination of a UV short-pulse laser (355 nm, 6 ns) for fluorescence excitation with a 10-100 ns short-time synchronous detection using a gated image-intensified multi-channel CCD of the fluorescence made the LIFS lidar operation possible even in daytime. The LIFS lidar with this construction demonstrated the potential of natural river/lake water quality monitoring at the Tenryu River/Lake Suwa. Three main components in the fluorescence data of the water, dissolved organic matter, phycocyanin, and chlorophyll, were extracted by spectral analysis using the standard spectral functions of these components. Their concentrations were estimated by adapting experimentally calibrated data. Results of long-term field observations using our LIFS lidar from 2010 to 2012 show the necessity of simultaneous multi-component detection to understand the natural water environment.

Sudden reversible pacemaker failure in a patient with cardiac sarcoidosis: an unfortunate case of ventricular septal pacing.

We report a case of sudden marked deterioration of ventricular stimulation threshold resulting in pacemaker failure 16 months after a ventricular septal lead implantation for atrioventricular block. Echocardiography revealed septal wall thinning at the electrode-tissue interface, which was not detected pre-operatively. Endomyocardial biopsy confirmed cardiac sarcoidosis. The increased threshold was reversible with prednisolone.

In-hospital monitoring of T-wave alternans in a case of amiodarone-induced torsade de pointes: clinical and methodologic insights.

We report a case of macroscopic T-wave alternans occurring 30 min before the onset of amiodarone-induced torsade de pointes, illustrating a means to monitor for proarrhythmia.

Left atrial pathological degeneration assessed by integrated backscatter transesophageal echocardiography as a predictor of progression to persistent atrial fibrillation: results from a prospective study of three-years follow-up.

BACKGROUND: It is recognized that one of the causes of atrial fibrillation (AF) is pathological degeneration of the left atrium (LA). However, prospective study that elucidated the relationship between the incidence of persistent AF and pathological degeneration has not been performed. The purpose of this study was to elucidate the usefulness of integrated backscatter (IBS) values for the prediction of progression from paroxysmal AF (PAF) to persistent AF. METHODS: We measured IBS values of the entire LA wall at 5 mm intervals (except the posterior wall) in 27 patients with paroxysmal AF and evaluated progression to persistent AF for three years. IBS values were acquired with transesophageal echocardiography (TEE) using a 4-7 MHz transducer. IBS values were calculated as the average power of the backscattered signal from regions of interest (ROI). Each IBS value was color-coded to construct three dimensional maps. RESULTS: Average IBS values of total voxels in color-coded maps in the persistent AF group were significantly greater than those in the non-persistent AF group (25.8 ± 5.0 dB vs. 17.4 ± 10.2 dB, p = 0.047), whereas there was no significant difference in LA diameter between the persistent AF and the non-persistent AF group. There was significant difference in persistent AF-free survival after the baseline measurements in the subjects stratified by IBS value (< 20 dB versus ≥ 20 dB) (univariate Cox regression analysis: hazard ratio: 8.74, p =0.046). CONCLUSION: Using IBS values measured by TEE, we can identify an increase in atrial degeneration that may predict the occurrence of persistent AF before LA dilation.

Relationship among coronary plaque compliance, coronary risk factors and tissue characteristics evaluated by integrated backscatter intravascular ultrasound.

BACKGROUND: The purpose of the present study was to evaluate the mechanical properties of coronary plaques and plaque behavior, and to elucidate the relationship among tissue characteristics of coronary plaques, mechanical properties and coronary risk factors using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS: Non-targeted plaques with moderate stenosis (plaque burden at the minimal lumen site: 50-70%) located proximal to the site of the percutaneous coronary intervention target lesions were evaluated by IB-IVUS. Thirty-six plaques (less calcified group: an arc of calcification ≤10°) in 36 patients and 22 plaques (moderately calcified group: 10° < an arc of calcification ≤60°) in 22 patients were evaluated. External elastic membrane volume (EEMV) compliance, lumen volume (LV) compliance, plaque volume (PV) response (difference between PV in systole and diastole), EEM area stiffness index were measured at the minimal lumen site. Relative lipid volume (lipid volume/internal elastic membrane volume) was calculated by IB-IVUS. RESULTS: In the less calcified group, there was a significant correlation between EEMV compliance and the relative lipid volume (r = 0.456, p = 0.005). There was a significant inverse correlation between EEM area stiffness index and the relative lipid volume (p = 0.032, r = -0.358). The LV compliance and EEM area stiffness index were significantly different in the diabetes mellitus (DM) group than in the non-DM group (1.32 ± 1.49 vs. 2.47 ± 1.79%/10 mmHg, p =0.014 and 28.3 ± 26.0 vs. 15.7 ± 17.2, p =0.020). The EEMV compliance and EEM area stiffness index were significantly different in the hypertension (HTN) group than in the non-HTN group (0.77 ± 0.68 vs. 1.57 ± 0.95%/10 mmHg, p =0.012 and 26.5 ± 24.3 vs. 13.0 ± 16.7, p =0.020). These relationships were not seen in the moderately calcified group. CONCLUSION: The present study provided new findings that there was a significant correlation between mechanical properties and tissue characteristics of coronary arteries. In addition, our results suggested that the EEMV compliance and the LV compliance were independent and the compliance was significantly impaired in the patients with DM and/or HTN. Assessment of coronary mechanical properties during PCI may provide us with useful information regarding the risk stratification of patients with coronary heart disease.

Comparison between integrated backscatter intravascular ultrasound and 64-slice multi-detector row computed tomography for tissue characterization and volumetric assessment of coronary plaques.

BACKGROUND: The purpose of this study was to determine the cut-off values of Hounsfield units (HU) for the discrimination of plaque components and to evaluate the feasibility of measurement of the volume of plaque components using multi-detector row computed tomography (MDCT). METHODS: Coronary lesions (125 lesions in 125 patients) were visualized by both integrated backscatter intravascular ultrasound (IB-IVUS) and 64-slice MDCT at the same site. The IB values were used as a gold standard to determine the cut off values of HU for the discrimination of plaque components. RESULTS: Plaques were classified as lipid pool (n =50), fibrosis (n =65) or calcification (n =35) by IB-IVUS. The HU of lipid pool, fibrosis and calcification were 18 ± 18 HU (-19 to 58 HU), 95 ± 24 HU (46 to 154 HU) and 378 ± 99 HU (188 to 605 HU), respectively. Using receiver operating characteristic curve analysis, a threshold of 50 HU was the optimal cutoff values to discriminate lipid pool from fibrosis. Lipid volume measured by MDCT was correlated with that measured by IB-IVUS (r =0.66, p <0.001), whereas fibrous volume was not (r =0.21, p =0.059). CONCLUSION: Lipid volume measured by MDCT was moderately correlated with that measured by IB-IVUS. MDCT may be useful for volumetric assessment of the lipid volume of coronary plaques, whereas the assessment of fibrosis volume was unstable.

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors.

PURPOSE: Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors. METHODS: Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed. RESULTS: Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3-77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1. CONCLUSIONS: This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified. TRIAL REGISTRATION: Clinical Trials.gov number: NCT03006887.

Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome.

AIMS: T-wave alternans (TWA) can precede onset of ventricular tachyarrhythmia (VTA). We evaluated the usefulness of continuous TWA monitoring in ultra-short-term prediction of impending life-threatening VTA upon emergent reperfusion in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: Twenty consecutive ACS patients undergoing emergent reperfusion therapy were studied. Continuous ambulatory electrocardiograms (ECGs) (leads V1 and V5) were recorded during emergency room visit and therapy. Peak TWA was determined before and after reperfusion by the modified moving average method. Coronary balloon angioplasty/stenting was successfully performed in 19 patients and intracoronary vasodilator was administered in 1 patient with coronary spasm. Three (15.0%) patients developed VTA requiring cardioversion soon after reperfusion. Peak TWA before reperfusion was higher in patients with VTA than in those without (33.0 ± 4.4 vs. 15.8 ± 4.0 µV, P < 0.001). Two patients with arrhythmia exhibited an upsurge in TWA to 75 and 105 µV before onset of VTA. In the third patient, macroscopic TWA appeared in leads V1-V4 in a 12-lead ECG prior to VTA upon pharmacological resolution of vasospasm, although the ambulatory ECG field of view could not detect the upsurge. CONCLUSION: Acute coronary syndrome patients at risk of developing VTA soon after reperfusion exhibit premonitory episodes of increased TWA. Thus, TWA monitoring may be useful for ultra-short-term prediction of life-threatening cardiac arrhythmia risk upon emergent reperfusion in ACS patients. Continuous 12-lead ECGs may be required to optimize detection of TWA, which is regionally specific.