Expression and mutation statuses of epidermal growth factor receptor in thymic epithelial tumors

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations have been reported to correlate with the sensitivity to the tyrosine kinase inhibitor treatment for advanced lung cancers. Since several reports have shown that invasive thymoma overexpress the EGFR protein, we examined the EGFR expression and mutation statuses in thymoma and thymic carcinoma tissues. METHODS: EGFR mutation statuses from 99 thymic epithelial tumor samples were evaluated by a rapid and sensitive TaqMan assay using Applied Biosysytems 7500 real-time PCR system. Probes were designed according to the 13 different EGFR mutations reported previously in lung cancers. A total of 38 thymoma samples were directly sequenced for the EGFR gene. Protein expressions were evaluated for 56 thymic epithelial tumors by immunohistochemistry. RESULTS: EGFR gene mutations were not detected in any of the thymoma and thymic cancer samples using TaqMan PCR assay. Of the 38 samples 3 showed a heterozygous silent mutation without changes in the protein, a G to A transition at the nucleotide 2361 in exon 18. EGFR expression was significantly higher in invasive thymomas (stages III-IV, 15/19 were positive) than in early stage thymomas (stages I-II, 7/33 were positive) (P < 0.0001). All four carcinomas and all seven B3 thymomas showed EGFR positive staining. CONCLUSIONS: Although EGFR mutation at the tyrosine kinase domain is unlikely to be a therapeutic target for thymoma, the information about EGFR expression would contribute to the further identification of the therapeutic target for advanced thymomas.     

A planar catechin analogue having a more negative oxidation potential than (+)-catechin as an electron transfer antioxidant against a peroxyl radical

The hydrogen transfer reaction of antioxidative polyphenol with reactive oxygen species has proved to be the main mechanism for radical scavenging. The planar catechin (P1H(2)), in which the catechol and chroman structure in (+)-catechin (1H(2)) are constrained to be planar, undergoes efficient hydrogen atom transfer toward galvinoxyol radical, showing an enhanced protective effect against the oxidative DNA damage induced by the Fenton reaction. The present studies were undertaken to further characterize the radical scavenging ability of P1H(2) in the reaction with cumylperoxyl radical, which is a model radical of lipid peroxyl radical for lipid peroxidation. The kinetics of hydrogen transfer from catechins to cumylperoxyl radical has been examined in propionitrile at low temperature with use of ESR, showing that the rate of hydrogen transfer from P1H(2) is significantly faster than that from 1H(2). The rate was also accelerated by the presence of Sc(OSO(2)CF(3))(3). Such an acceleration effect of metal ion indicates that the hydrogen transfer reaction proceeds via metal ion-promoted electron transfer from P1H(2) to oxyl radical followed by proton transfer rather than via a one-step hydrogen atom transfer. The electrochemical ease of P1H(2) for the one-electron oxidation investigated by second-harmonic alternating current voltammetry strongly supports the two step mechanism for hydrogen transfer, resulting in the enhanced radical scavenging ability.     

The results of liver cryosurgery for synchronized liver metastasis from colorectal cancer

We examined our results of liver cryosurgery for synchronized liver metastasis from colorectal cancer. Twelve patients whose prognosis after the cryosurgery was clear were eligible. All of the patients received not only a resection of the colorectal primary lesion, but they also received a cryosurgery for liver metastases under the same laparotomy. These patients had been treated in this manner from 1981 to 1987. Ten of the 12 patients died from recurrent cancer. The range in survival time of 12 cases was from 6 months to 117 months, and the average survival length was 25.4 months. The examination of the results suggested that there were no cryosurgery induced anti-immunological response observed among the patients. The survival lengths of the patients with untreated cancer were good.     

Phase II study of OK-432 intrapleural administration followed by systemic cisplatin and gemcitabine for non-small cell lung cancer with pleuritis carcinomatosa

We conducted a phase II study of OK-432 intrapleural administration followed by systemic chemotherapy using cisplatin with gemcitabine to determine their combined effects on non-small cell lung cancer (NSCLC) with pleuritis carcinomatosa. Between December 1999 and October 2001, 15 patients were registered in the study. Fourteen patients had an Eastern Cooperative Oncology Group performance status (PS) of 1, and one patient had a PS of 2. Ten patients had adenocarcinoma, one had squamous cell carcinoma, and four had malignant mesothelioma. Patients underwent thoracocentesis and received an OK-432 intrapleural injection. They were then treated every three weeks with chemotherapy consisting of 80 mg/m2 cisplatin on day 1 and 1000 mg/m2 gemcitabine on days 1 and 8. Thirteen patients received two or more courses of chemotherapy. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in five, two and three patients, respectively. Non-hematological toxicities were mild, except for one patient who experienced a grade 3 elevation of transaminase and two patients who experienced grade 3 nausea. Of the 15 patients, one achieved partial response (PR), 13 a stable disease (SD) rating, and one a progressive disease (PD) rating, and the overall response rate was 6.7%. The median survival time was 13.5 months and the one-year survival rate was 60.0%. In conclusion, OK-432 intrapleural administration followed by cisplatin and gemcitabine systemic chemotherapy did not reduce patients' tumors but did prolong their survival time. A large-scale phase II study of the efficacy of this combination therapy is required.     

A planar catechin analogue as a promising antioxidant with reduced prooxidant activity

A planar catechin analogue (1H2), in which catechol and chroman moieties in (+)-catechin are constrained to be coplanar, is an efficient radical scavenger compared to the native catechin, and are nearly as effective as quercetin, a strong radical scavenger. The dianion (1(2-)) of 1H2 produced by the reaction of 1H2 with 2 equiv of tetramethylammonium methoxide reduced molecular oxygen (O2) to generate superoxide anion (O2*-). The resulting radical anion (1*-) from 1H2 underwent intramolecular proton transfer to give an o-semiquinone radical anion form of 1*-, which shows a characteristic ESR spectrum with g value of 2.0048. Although the same mechanism has also been shown for (+)-catechin, the rate constant of electron transfer (ket) from 1(2-) to O2 is about a half of that reported for (+)-catechin, indicating that the electron transfer from 1(2-) to O2 is slower than that from (+)-catechin dianion to O2. Together with efficient protection against DNA strand breakage induced by the Fenton reaction, the small ket value for 1H2 implies that, in physiologically relevant systems, there is less of a possibility of generating oxygen radicals responsible for prooxidant activity with 1H2 than that with (+)-catechin. The strong radical scavenging ability and less-efficient generation of O2*- suggest that the planar catechin analogue may be useful for the prevention and/or treatment of free-radical-associated diseases.     

Inhibition and facilitation by pimobendan,a calcium sensitizer,of catecholamine secretion from bovine adrenal chromaffin cells

The effects of pimobendan, a Ca(2+) sensitizer with inhibitory action against cyclic-GMP-inhibited phosphodiesterase (PDE-III), on catecholamine (CA) secretion were studied in bovine adrenal chromaffin cells. In intact cells, pimobendan (10 - 100 microM) inhibited CA secretion stimulated by acetylcholine (10 and 30 microM) and 1,1-dimethyl-4-phenyl-piperazinium (DMPP) (3 and 10 microM), but facilitated CA secretion stimulated by high K(+) (30 mM), histamine (3 microM), and angiotensin-II (3 microM). Histamine and angiotensin-II had no effect on CA secretion in Ca(2+)-free medium. The inhibition or facilitation by pimobendan of the stimulation-evoked CA secretion was not affected by H-89 (1 microM) and H-8 (30 microM), inhibitors of cyclic-AMP-dependent protein kinase. Milrinone (10 and 30 microM) and amrinone (100 and 300 microM), inhibitors of PDE-III, did not affect the stimulation-evoked CA secretion. In beta-escin-permeabilized cells, pimobendan (10 - 100 microM) did not affect CA secretion stimulated by Ca(2+) (0.1 - 10 microM) in the presence and absence of MgATP (2 mM). These results indicate that pimobendan has dual effects, inhibition and facilitation, on CA secretion. The inhibition may be due to an inhibitory action on nicotinic receptors and the facilitation may be due to a facilitatory action on stimulation-induced Ca(2+) influx. Neither Ca(2+) sensitizing nor PDE-III inhibiting actions seem to be related to these effects.     

Pleiotropic effects of cytokines on acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction

Many cytokines have been reported to be increased in human and animal models with cardiovascular diseases. Myocardial infarction (MI) is accompanied with an inflammatory reaction which induces cardiac dysfunction and remodeling. The inflammatory reaction has been investigated in animal models of MI or myocardial ischemia-reperfusion injury. The mechanisms by which cytokine cascade is activated in the infarcted myocardium have been recently elucidated. Several hematopoietic growth factors including interleukin-3 (IL-3), IL-6, granulocyte-macrophage colony-stimulating factors (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) have been reported to be positive regulators of granulopoiesis and act at different stages of myeloid cell development. G-CSF plays a critical role in regulation of proliferation, differentiation, and survival of myeloid progenitor cells. G-CSF also causes a marked increase in the release of hematopoietic stem cells (HSCs) into the peripheral blood circulation, a process termed mobilization. Although cardiac myocytes have been considered as terminally differentiated cells, it has been recently reported that there are many proliferating cardiac myocytes after MI in human heart. After it was demonstrated that bone marrow stem cells (BMSCs) can differentiate into cardiac myocytes, myocardial regeneration has been widely investigated. Recently, G-CSF has been reported to improve cardiac function and reduces mortality after acute MI. Although the mechanism by which G-CSF ameliorates cardiac dysfunction is not fully understood, there is the possibility that G-CSF may regenerate cardiac myocytes and blood vessels through mobilization of BMSCs. In the future, cytokine-mediated regeneration therapy may become to be a novel therapeutic strategy for MI.     

Therapeutic options which potentially cure patients with thymoma

This study reports clinicopathologic features, treatment, and outcome of 107 thymomas, especially focusing on a combined modality program using hemithorax irradiation (HI) and restaging surgery using corticosteroid for advanced thymoma showing disseminative lesions. The use of HI after presumably total resection of the dissemination under posterolateral thoracotomy had no effect on reducing the incidence of relapsing. On the other hand, our own experience revealed that corticosteroid caused degenerative changes in the epithelial cells and lymphocytes of thymomas. The fact led us administer corticosteroid not only in preoperative setting but during postoperative HI. A better prognosis may be anticipated, although the follow up period is short and the number of patients involved is small.