A Randomized Cross-over Study of High-dose Metoclopramide plus Dexamethasone versus Granisetron plus Dexamethasone in Patients Receiving Chemotherapy with High-dose Cisplatin

We carried out a randomized, single-blind, cross-over trial to compare the antiemetic effect, for both acute and delayed emesis, of granisetron plus dexamethasone (GRN+Dx) with that of high-dose metoclopramide plus dexamethasone (HDMP + Dx). Fifty-four patients with primary or metastatic lung cancer, given single-dose cisplatin (> 80 mg/m²) chemotherapy more than twice, were enrolled in this study. They were treated with both HDMP+Dx and GRN+Dx in two consecutive chemotherapy courses. On day 1, patients experienced a mean of 2.5 (SD=4.3) and 0,1 (SD = 0.4) episodes of vomiting in the HDMP+Dx and the GRN + Dx groups, respectively ( P =0.0008). Complete response rate on day 1 was 45 and 90% in the HDMP+Dx and the GRN+Dx groups, respectively ( P = 0.0001). Patients treated with GRN+Dx had a tendency to suffer more episodes of vomiting than the HDMP+Dx group on days 2–5, but it was not statistically significant. Twenty-four patients (57%) preferred the GRN+Dx treatment and 14 patients (33%), HDMP + Dx. In the HDMP + Dx group, nine patients (21%) had an extrapyramidal reaction, and 5 patients (12%) had constipation that lasted for at least two days. In contrast, no patients had extrapyramidal reactions, and IS patients (43%) had constipation in the GRN+Dx group ( P < 0.01). GRN+Dx was more effective than HDMP+Dx only in preventing the acute emesis induced by cisplatin. An effective treatment for delayed emesis is still needed.     

CPT-11: Population Pharmacokinetic Model and Estimation of Pharmacokinetics Using the Bayesian Method in Patients with Lung Cancer

In this study, we aimed to develop a population pharmacokinetic model for CPT-11 and to use the Bayesian method to estimate CPT-11 pharmacokinetic parameters in each of 43 patients who received combined therapy consisting of CPT-11 and etoposide. The group was divided into first and second data sets of 30 and 13 patients, respectively. We developed a population pharmacokinetic model of CPT-11 based on the first data set. The individual pharmacokinetic parameters [area under the concentration curve (AUC) and clearance (CD] were subsequently estimated by using the Bayesian method on the second data set. Plasma CPT-11 concentrations were measured by high-performance liquid chromatography, and compartmental pharmacokinetic models were fitted by the Bayesian method. The population pharmacokinetic model was developed by using the nonlinear mixed effect model. We selected the volume of the central compartment (Vc), CL, and distribution rate constants (K12, K21) as population pharmacokinetic parameters. The population mean values (CV%) of Vc, CL, K12, and K21 were, respectively, 31.8 (15.7%) liter/m²,14.1 (27.8%) liter/h/m²,1.1 (8.4%)/h, and 0.41 (30.3%)/h. Residual intraindivirtual variability was 22.9%. The optimal sampling regime for estimation of the AUC and CL in using the Bayesian method was the two time points of 1 and 8 h post infusion. The mean predictive error, the mean absolute predictive error, and the root mean squared error were -3.3, 9.4, 3.2% (AUC) and 6.3, 10.0, 3.5% (CL), respectively. We concluded that the AUC and CL of CPT-11 could be estimated from plasma concentrations at two times by using the Bayesian method.     

Flow cytometric estimation on cytotoxic activity of leaf extracts from seashore plants in subtropical Japan: isolation,quantification and cytotoxic action of (-)-deoxypodophyllotoxin

The cytotoxic activity of methanol extracts of leaves collected from 39 seashore plants in Iriomote Island, subtropical Japan was examined on human leukaemia cells (K562 cells) using a flow cytometer with two fluorescent probes, ethidium bromide and annexin V-FITC. Five extracts (10 microg/mL) from Hernandia nymphaeaefolia, Cerbera manghas, Pongamia pinnata, Morus australis var. glabra and Thespesia populnea greatly inhibited the growth of K562 cells. When the concentration was decreased to 1 microg/mL, only one extract from H. nymphaeaefolia still inhibited the cell growth. A cytotoxic compound was isolated from the leaves by bioassay-guided fractionation and was identified as (-)-deoxypodophyllotoxin (DPT). The fresh leaves of H. nymphaeaefolia contained a remarkably high amount of DPT (0.21 +/- 0.07% of fresh leaf weight), being clarified by a quantitative HPLC analysis. DPT at 70-80 pM started to inhibit the growth of K562 cells in an all-or-none fashion and at 100 pM or more it produced complete inhibition in all cases. Therefore, the slope of the dose-response curve was very steep. DPT at 100 pM or more decreased the cell viability to 50%-60% and increased the number of cells undergoing apoptosis (annexin V-positive cells). The results indicate that DPT contributes to the cytotoxic action of the extract from the leaves of H. nymphaeaefolia on K562 cells.     

Changes in repolarization properties with long-term cardiac memory modify dispersion of repolarization in patients with Wolff-Parkinson-White syndrome

INTRODUCTION: Transient T wave changes after cessation of preexcitation have been attributed to cardiac memory. However, there have been no reports on the effects of long-term cardiac memory on repolarization dispersion before and after catheter ablation in patients with Wolff-Parkinson-White (WPW) syndrome. METHODS AND RESULTS: We investigated 47 patients with an accessory pathway (AP; 24 manifest left-sided, 14 manifest right-sided, and 9 concealed left-sided). Repolarization dispersion was analyzed by two methods, recovery time (RT) dispersion and newly proposed T wave width (WT), from 87-lead body surface maps before, 1 day after, and 7 days after catheter ablation. RT dispersion and WT were significantly correlated before, 1 day after, and 7 days after catheter ablation (r = 0.78). In patients with preexcitation, RT dispersion and WT increased significantly (P < 0.05) 1 day after catheter ablation (178 +/- 32 msec and 172 +/- 30 msec) compared with those before (154 +/- 24 msec and 156 +/- 18 msec) and 7 days after catheter ablation (147 +/- 19 msec and 156 +/- 16 msec), respectively. However, there were no significant changes in RT dispersion and WT before and after catheter ablation in concealed WPW syndrome. CONCLUSION: The findings suggest that the abrupt changes in activation sequence increase repolarization dispersion in the presence of previous cardiac memory, and that the dispersion decreases days or weeks after alteration of activation sequence by catheter ablation, with development of new cardiac memory in patients with manifest WPW syndrome.     

Detection of hypervascular hepatocellular carcinoma by dynamic magnetic resonance imaging with double-echo chemical shift in-phase and opposed-phase gradient echo technique: comparison with dynamic helical computed tomography imaging with double arterial phase

PURPOSE: The technique of double-echo chemical shift gradient echo magnetic resonance imaging (MRI) with the fast low-angle shot (double-echo FLASH) sequence provides in-phase and opposed-phase images in a single breath hold. The purpose of this study was to evaluate the efficacy of dynamic MRI with double-echo FLASH imaging for the detection of hypervascular hepatocellular carcinoma by comparing it with dynamic helical computed tomography (CT) imaging with double arterial phase. MATERIALS AND METHODS: Twenty-nine patients with 67 hypervascular hepatocellular carcinoma nodules who underwent both dynamic MRI with double-echo FLASH imaging (repetition time/echo time/flip angle: 160/3.6, 7.0/80 degrees ) and dynamic helical CT imaging with double arterial phase were enrolled in the study. For dynamic MRI, precontrast, arterial, portal venous, and equilibrium phase images were obtained before and approximately 19, 60, and 120 seconds, respectively, after intravenous injection of 0.1 mmol/kg of gadopentetate dimeglumine at a rate of 2 ml/s. For dynamic CT imaging, quadraphase images, including early arterial, late arterial, portal venous, and equilibrium phases, were obtained serially approximately 20, 30, 70, and 180 seconds, respectively, after intravenous administration of 2 ml/kg of 300 mgI/ml of nonionic contrast medium at a rate of 5 ml/s. Three masked observers independently interpreted images obtained with each technique in random order, separately and without patient identifiers. Sensitivity and positive predictive values as well as the area below the alternative-free response receiver operating characteristic curve (Az) for each imaging technique were calculated and compared statistically. RESULTS: Mean sensitivity and positive predictive values of MRI for hypervascular hepatocellular carcinoma were 48% and 94%, respectively, and those of CT imaging were 47% and 91%, respectively. In 11 (38%) of the 29 patients, at least one observer judged dynamic MRI to be superior, whereas in 5 patients (17%), dynamic CT was judged to be superior. There was no significant difference in the sensitivity and positive predictive values between these techniques (p > 0.05). There was no significant difference either in mean Az values between CT (0.55) and MRI (0.57) (p = 0.61). CONCLUSION: Dynamic MRI with double-echo FLASH imaging can detect hypervascular hepatocellular carcinoma as well as dynamic helical CT imaging with double arterial phase.     

High dose rate endovascular brachytherapy in aorto-iliac lesion for the prevention of restenosis

This study examined the applicability of endovascular brachytherapy to larger del arteries such as the abdominal aorta and iliac artery. Endovascular brachytherapy using an Ir-192 HDR source was administered 11 times to nine patients who had undergone percutaneous transluminal angioplasty (PTA) between 1995 and 1999. The follow-up lasted 13 to 55 months after treatment (median, 24 months). Eight of the 11 lesions have been controlled so far. Although one case developed thrombus inside the stent five months later, recanalization was achieved by means of retreatment. One patient who underwent low-dose irradiation (6 Gy) without stent implantation showed restenosis five months after treatment. We used a centering catheter that did not block the blood stream for exact centering of the radiation source in larger vessels such as the abdominal aorta. Although endovascular brachytherapy is a promising and safe procedure, careful follow-up is needed to detect untoward reactions such as thrombosis.     

The usefulness of 1.5 harmonic imaging ultrasonography with Levovist in the diagnosis of focal hepatic tumors

In contrast-enhanced 1.5 harmonic imaging sonography, images are obtained in a band intermediate between the fundamental and the 2nd harmonic components. In the present study, we investigated the usefulness of 1.5 harmonic imaging sonography with the use of the contrast agent Levovist for the diagnosis of hepatocellular carcinoma (HCC), metastatic hepatic tumor, and hepatic hemangioma. The subjects in this study were 64 patients with 70 nodules of hepatic tumors (42 nodules in 36 cases of hepatocellular carcinoma, 20 nodules in 20 cases of metastatic hepatic tumor, and 8 nodules in 8 cases of hepatic hemangioma). Contrast enhancement of tumors acquired in the early, portal, and late phases with 1.5 harmonic imaging sonography were compared to classify the tumors. 1.5 harmonic imaging sonography of HCC showed contrast enhancement of 36 nodules (85.7%). Hypervascular enhancement in the early phase, which was maintained in the portal phase, changed to images with no contrast enhancement with partial persistence of contrast enhancement in the late phase. 1.5 harmonic imaging sonography of metastatic hepatic tumor showed hypervascular enhancement of the margin of 20 nodules (100%) in the early and portal phases, which changed to images with no contrast enhancement in the late phase. 1.5 harmonic imaging sonography of hepatic hemangiomas maintained hypervascular enhancement on the tumor margin of 5 nodules (62.5%) in the early and portal phases. When early phase 1.5 harmonic imaging sonography did not show hypervascular enhancement in 3 nodules (37.5%), and late-phase images confirmed that these 3 nodules were hypervascular enhancement on the tumor margin. 1.5 harmonic imaging sonography of hepatic tumors (hepatocellular carcinoma, metastatic hepatic tumor and hepatic hemangioma) provided characteristic findings of contrast enhancement in the early, portal, and late phases, and will contribute to differential diagnosis.     

A case of hepatocellular carcinoma initially treated by carbon ions, followed by protons for marginal recurrence with portal thrombus

We report a case of hepatocellular carcinoma (HCC), initially treated by carbon ions, then subsequently by protons for marginal recurrence. A 52-year-old man with stage II HCC was enrolled in the clinical study for carbon ion therapy. A total dose of 52.5 GyE in 8 fractions was delivered through a right lateral port for 13 days. Dynamic CT performed 7 months after the initiation of carbon ion therapy showed a decrease in the size of the tumor. Dynamic CT performed 12 months after the therapy revealed marginal recurrence of HCC accompanied with portal vein tumor thrombus (PVTT). Proton therapy of 66 GyE in 22 fractions was delivered through posterior and right lateral ports for 33 days. Dynamic CT performed 3 months after the initiation of proton therapy showed a regression of the recurrent tumor and disappearance of the PVTT. No serious adverse effects were observed during or after these two treatments. He was free from further recurrence 27 months after the initiation of the first carbon ion therapy. Both carbon ions and protons were effective with minimal side effects.     

Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance

The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3'-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3'-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.