Cyclosporin-A enhances docetaxel-induced apoptosis through inhibition of nuclear factor-kappaB activation in human gastric carcinoma cells.

PURPOSE: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]- induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-kappaB (NF-kappaB) activation. EXPERIMENTAL DESIGN: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-kappaB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. RESULTS: A combination of CsA (5 micro M) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-kappaB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-kappaB decoy, a well-known NF-kappaB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. CONCLUSIONS: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.     

Phase I trial of GBS‐01 for advanced pancreatic cancer refractory to gemcitabine

GBS‐01, an extract from the fruit of Arctium lappa L. is an orally administered drug rich in arctigenin, which has been reported to exert antitumor activity by attenuating the tolerance of cancer cells to glucose deprivation. We investigated the maximum tolerated dose of GBS‐01 based on the frequency of the dose‐limiting toxicities (DLTs) and pharmacokinetics in patients with advanced pancreatic cancer refractory to gemcitabine. GBS‐01 was given orally at escalating doses from 3.0 g (containing 1.0 g burdock fruit extract) to 12.0 g q.d. A DLT was defined as a grade 4 hematological toxicity and grade 3 or 4 non‐hematological toxicity appearing during the first 28 days of treatment. Fifteen patients (GBS‐01 dose level 1 [3.0 g], three patients; dose level 2 [7.5 g], three patients; and dose level 3 [12.0 g], nine patients) were enrolled. None of the patients at any of the three dose levels showed any sign of DLTs. The main adverse events were increased serum γ‐glutamyl transpeptidase, hyperglycemia, and increased serum total bilirubin; however, all the toxicities were mild. Of the 15 patients, 1 showed confirmed partial response and 4 patients had stable disease. The median progression‐free and overall survival of the patients were 1.1 and 5.7 months, respectively. The pharmacokinetic study revealed a high bioavailability of arctigenin and rapid conjugation of the drug with glucuronic acid. The recommended dose of GBS‐01 was 12.0 g q.d, and favorable clinical responses were obtained. This trial was registered at UMIN‐CTR ( http://www.umin.ac.jp/ctr/index-j.htm ), identification number UMIN000005787.     

Localization of small bowel bleeding by arterial injection of Tc-99m-labeled RBC

A 79-year-old man with melena was suspected of having small bowel bleeding because upper and lower endoscopic findings were negative. Technetium-99m-labeled red blood cell (Tc-99m-RBC) scintigraphy was performed by arterial injection of a radiotracer from the superior mesenteric artery (SMA) after angiography. Extravasation was seen in the ileum by scintigraphy although angiography was negative. Scintigram 2 minutes after arterial injection was consistent with the late capillary phase of balloon occluded angiography. This comparison provided a better anatomical distinction. Tc-99m-RBC scintigraphy by arterial injection through the SMA identified the bleeding site in the small bowel more accurately than conventional intravenous Tc-99m-RBC scintigraphy.     

Current status of development and in vivo evaluation of the National Cardiovascular Center electrohydraulic total artificial heart system

We have been developing an electrohydraulic total artificial heart system. The system has a pumping unit, consisting of diaphragm-type blood pumps and an energy converter, and an electronics unit, consisting of an internal controller, an internal battery, and transcutaneous energy transfer and optical telemetry subunits. The energy converter, designed to be placed outside the pericardial space, reciprocates and delivers hydraulic silicone oil to the alternate blood pumps through a pair of flexible oil conduits. The left-right output balance is achieved with an interatrial shunt made in the composite atrial cuff. In vivo performance of the pumping unit has been evaluated by chronic implantation of 16 calves weighing 54–88 kg. Five calves survived for more than a week, and the longest-surviving animal lived for over 12 weeks until its accidental death. In this animal, a cardiac output of 6–81/min was maintained by the device with power consumption of 13.5±0.9W and 9%–11% efficiency. The left and right atrial pressures were 16±4 and 14±4 mm Hg, respectively, and the left-right output difference was adequately balanced with the interatrial shunt. The mixed venous oxygen saturation was 65±6% and the serum lactate level was 5±1 mg/dl, representing favorable oxygen metabolic conditions. The temperatures of the energy converter and the blood pump surfaces were 39.4±0.7° and 38.8±1.5°C, respectively, indicating that heat generation and dissipation were acceptable. The serum and tissue silicon levels were within normal (<1 μg/ml or <1 μg/g), indicating that permeation of silicone oil through the blood pump diaphragm was inconsequential and unlikely to be detrimental. We conclude that the system has the potential to be a totally implantable cardiac replacement.     

Precut technique using an injection needle: A retrospective study on a new ancillary procedure for pleural biopsy

The effectiveness of thoracoscopic biopsy as a diagnostic method for pleural diseases has been reported; however, obtaining a sufficient specimen size is sometimes difficult. Therefore, an ancillary technique, the precut technique using an injection needle, was devised to address this problem. This study aimed to evaluate the effectiveness and safety of the novel precut technique in patients with undiagnosed pleural effusion.This retrospective study included 22 patients who underwent pleural biopsy using the precut technique to examine exudative pleural effusion of unknown etiology. Thoracoscopy was performed under local anesthesia. The biopsy procedure was performed as follows: a needle was inserted into the pleura around the lesion using a semiflexible thoracoscope; the needle was positioned to make an incision in the pleura while injecting 1% lidocaine with epinephrine and lifting the pleura from the fascia; 2 or 3 precut incision lines were arranged in a triangle; and the specimen was obtained from the parietal pleura using forceps or a cryoprobe. Patient data including age, number of biopsies, biopsy specimen size, pathological and final diagnosis, and postoperative complications were examined.All patients were male with an average age of 74 years. Pleural effusion was found on the right and left sides in 16 and 6 patients, respectively. The average major axis of the biopsy specimens was 18 mm (range, 10–30 mm), which was sufficient to establish a pathological diagnosis. Only 1 patient experienced minor temporal bleeding as a complication.The precut technique enabled the procurement of specimens sufficient in size for pleural biopsy.     

Clinical outcomes of concurrent chemoradiotherapy with volumetric modulated arc therapy in patients with locally advanced nasopharyngeal carcinoma

Purpose

The purpose of this study was to analyze the clinical results of concurrent chemoradiotherapy (CCRT) with volumetric modulated arc therapy (VMAT) for nasopharyngeal carcinoma (NPC) patients.

Materials and methods

Patients with stage II–IVB NPC who received CCRT with VMAT between 2010 and 2014 were included in this study. The planned dose was 70 Gy in 35 fractions.

Results

Twenty patients aged between 28 and 85 years (median 60 years) were assessed. With a median follow-up time of 47 months, the 3-year overall survival and progression-free survival rates were 85 and 65%, respectively. The 3-year local, regional and distant control rates were 78, 88 and 79%, respectively. At 0, 3, 6 and 12 months from CCRT, 19, 6, 3, and 1 patients had grade 2 dry mouth, respectively. No cases of grade 3 or worse dry mouth were observed. The severity of dry mouth was downgraded from grade 2 to grade 0 or 1 significantly earlier in younger patients (<70 years, p = 0.02) or patients in whom the mean dose to one parotid gland was lower (<26 Gy, p = 0.04).

Conclusions

Our clinical results regarding CCRT with VMAT for NPC patients showed favorable survival rates while maintaining organ function.

     

Whole-brain vascular reactivity measured by fMRI using hyperventilation and breath-holding tasks: efficacy of 3D prospective acquisition correction (3D-PACE) for head motion

Functional MR imaging (fMRI) study using hyperventilation and breath-holding task has been reported to be one of the non-invasive methods to examine whole-brain vascular reactivity. The purpose of this study was to evaluate the efficacy of a method for 3D prospective detection and correction of head motion (3D-PACE) in a study of whole-brain vascular reactivity using hyperventilation and breath-holding tasks. Eight healthy volunteers were scanned using an fMRI protocol of hyperventilation and breath-holding task blocks at 3 T in separate runs with and without 3D-PACE. In two subjects, two more runs with and without 3D-PACE were repeated. The mean total number of activated voxels ± standard deviation was 26,405.3±1,822.2 in the run with 3D-PACE and 17,329.9±2,766.3 in the run without 3D-PACE (P<0.05), although there is some intersubject variation regarding the effect of 3D-PACE. In the two subjects whose performed two more runs, the number of activated voxels were smaller in the run without 3D-PACE than even in the run with 3D-PACE performed later. We conclude that 3D-PACE is beneficial for fMRI studies of whole-brain vascular reactivity induced by hyperventilation and breath-holding.