Toshio Onitsuka

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (+/+) rats following periaortic application of calcium chloride (CaCl2) treatment but not in the mast cell–deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E–deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA.

Effect of mast cells on tumor angiogenesis in lung cancer

BACKGROUND We conducted a retrospective study to clarify the effect of mast cells on tumor angiogenesis in lung cancer patients. METHODS Formalin-fixed and paraffin-embedded tumor sections were used in this study. Parenchymal mast cells were stained with Alcian blue and safranin O. The number of mast cells per ten fields at a magnification of 200x was counted under light microscopy, and the average count was determined. To highlight the microvessels, endothelial cells were stained with anti-human factor VIII antibody. After the microvessel count was determined, the microvessels were further stained with Alcian blue and safranin O to show areas of mast cell infiltration. Expression of vascular endothelial growth factor was assessed using a polyclonal antibody. RESULTS We found a significant correlation between mast cell count and microvessel density. This correlation was also observed in patients with adenocarcinoma (p < 0.001) as well as in patients with squamous cell carcinoma (p < 0.01). Double staining of the microvessels showed highly angiogenic areas densely populated with mast cells. Although we detected a slight trend toward a correlation between vascular endothelial growth factor expression and microvessel density, it was not statistically significant. We found no association between vascular endothelial growth factor expression and mast cell count. CONCLUSIONS There appears to be a direct correlation between the number of mast cells and tumor angiogenesis in patients with lung cancer, and this relationship appears to be independent of vascular endothelial growth factor expression.

Intrapleural perfusion hyperthermo-chemotherapy for malignant pleural dissemination and effusion

Taking advantage of the antitumor effect of hyperthermia, we administered intrapleural perfusion hyperthermo-chemotherapy for the treatment of malignant pleural seeding or pleural effusion. This consists of irrigating the pleural space for 2 hours with 43 degrees C saline solution containing cis-platinum using specially devised extracorporeal circuits. From January 1988 through December 1993, we performed this technique in 12 patients with malignant disseminated lesions stemming from lung cancer who also underwent surgical resection of the primary lesions and in 7 patients with malignant pleural effusions who did not undergo thoracotomy or surgical resection. There were no serious clinical complications associated with this procedure. The pharmacokinetics showed that a high concentration of cis-platinum (more than 17.6 micrograms/mL in the free form) was retained in the pleural cavity during perfusion. After this therapy, the cancer cells showed marked degeneration with fibrosis in the pleural wall. The pleural effusion was well controlled in 100% of the patients. The median survival time in the 12 patients with pleural disseminated lesions who were treated with intrapleural perfusion hyperthermo-chemotherapy was 20 months. On the other hand, the median survival time in 7 patients with similar lesions who did not receive IPHC was only 6 months. Intrapleural perfusion hyperthermo-chemotherapy seems to have considerable value as an adjuvant therapy for patients with pleural dissemination who have had their primary lesions removed.

Prognostic impact of thrombocytosis in resectable non-small cell lung cancer

Relationship between thrombocytosis and poor prognosis has been reported in lung cancer. However, the majority of previous studies included many advanced stage and small cell lung cancer patients. Few studies focused on resectable non-small cell lung cancer patients. In the present study, therefore, consecutive 240 non-small cell lung cancer patients who received surgical resection were reviewed retrospectively, and investigated the survival impact of preoperative platelet count. In our results, the frequency of preoperative thrombocytosis was only 5.83% (14/240). The 5-year survival of patients with and without thrombocytosis was 28.87% and 63.73%, respectively. Both univariate and multivariate analyses indicated the independent prognostic impact of thrombocytosis. The present study is the first evaluation of prognostic effect of thrombocytosis in patients with resectable non-small cell lung cancer. Preoperative platelet count was a prognostic factor for resectable non-small cell lung cancer patients.

Correlation between mast cells and survival rates in patients with pulmonary adenocarcinoma

BACKGROUND A retrospective study on the correlation between mast cells and survival rates of 90 pulmonary adenocarcinoma patients is reported. METHODS Surgical specimens were stained with alcian blue and safranin O, and parenchymal mast cells were counted. Based on the counts, the patients were divided into two groups: Group A had mast cell counts of > 20/microscopic field; Group B, < 20. TNM staging and histological findings were recorded for both groups. Phenotypes of mast cells were determined using enzymehistochemistry. Total count numbers, the histological differentiation of adenocarcinomas, and phenotypes were evaluated with regard to patient survival rates. RESULTS Group A had a 5-year survival rate of 45.85%, as compared with Group Bs rate of 16.32% (P < 0.01). Group A also represented a higher percentage of well-differentiated adenocarcinomas. In both cancerous tissue and normal lung tissue, the predominant mast cell phenotype was MC(T). CONCLUSIONS There appears to be a direct relationship between the number of mast cells and clinical outcome in patients with pulmonary adenocarcinoma, even though the mast cells exhibited no significant phenotypic changes.

Beneficial effect of prostaglandin E1 on blood flow to the gastric tube after esophagectomy

BACKGROUND A prospective study on the vasodilatory effect of prostaglandin E1 on blood flow to the gastric tube after esophagectomy is reported. METHODS Twelve patients with thoracic esophageal cancer who underwent esophagectomy were enrolled in this study. In all patients, the esophagogastrostomy was performed in the cervical region, and the stomach was used for reconstruction. Immediately after the creation of the gastric tube, baseline blood flow was measured at the oral end, in the center, and at the pyloric ring of the gastric tube using a laser Doppler flowmeter. The prostaglandin E1 group (n = 6) was then infused with prostaglandin E1 until postoperative day 2; the control group (n = 6) received saline. At +5 minutes and +40 minutes after administration, blood flow was again measured at the same three sites. RESULTS The control group did not show a significant increase of blood flow to any site over time. For the prostaglandin E1 group, blood flow at +40 minutes increased from the baseline measurements significantly at a rate of 63%, 39%, and 36%, respectively. CONCLUSIONS Prostaglandin E1 has a characteristic vasodilating effect on the area of impaired microcirculation of the gastric tube, thereby increasing blood flow to the affected area.

Detection of Total Assist and Sucking Points Based on Pulsatility of a Continuous Flow Artificial Heart: In Vitro Evaluation

We investigated the basic characteristics of the pulsatility of motor current with an in vitro mock circuit that consists of a sac-type pulsatile pump (simulating the natural left ventricle), three reservoirs, and our mixed flow pump (MFP). There are three alternatives at the inlet of the MFP: 1) the left atrium (LA), 2) the left ventricle (LV), and 3) both (LALV). The motor current waveform was monitored. The pump speed of the MFP was changed from 0 to 7,000 rpm. We calculated the index of motor current amplitude (ICA), which was obtained from the amplitude of the motor current waveform divided by the simultaneous mean value. The ICA plotted against the pump speed had a peak point (t-point) that highly corresponded with the turning point from partial to total left heart assistance. The ICA also had a second specific point (s-point) that corresponded with the beginning of severe sucking. In LV and LALV aortic bypass, t- and s-points could clearly be detected. In LA aortic bypass, however, early and severe sucking occurred, and t- and s-points were not manifest. These data suggest that the assist status of continuous flow artificial heart can be estimated by detecting the t- and s-points.

Effect of hypothermic ischemia and reperfusion on calcium transport by myocardial sarcolemma and sarcoplasmic reticulum.

The effects of hypothermic ischemia and reperfusion on sarcolemma and sarcoplasmic reticulum Ca2+ transport were studied in vesicles isolated from rabbit hearts. Hypothermic global ischemia was produced by immersing hearts in saline at 4 degrees C for 3 h. Following hypothermic ischemia, reperfusion was carried out for 40 min using a Langendorff perfusion system for the working heart. Na+,K(+)-ATPase activity of sarcolemmal vesicles (SL), was not depressed by hypothermic ischemia nor by ischemia and reperfusion. The initial rate of Na(+)-Ca2+ exchange in SL vesicles was not depressed, but the maximum amount of Ca2+ uptake was increased both after hypothermic ischemia and after reperfusion. Ca2+ uptake activity of sarcoplasmic reticulum vesicles (SR) isolated from hearts subjected to hypothermic ischemia was slightly lower than that of control, and was further reduced following reperfusion. Ca(2+)-ATPase activity of SR was unaffected by hypothermic ischemia, while it was markedly lowered after reperfusion. Although the phosphoenzyme level in SR vesicles was slightly decreased, the turnover rate was reduced after reperfusion. Reperfusion injury thus took place mainly in SR while SL appeared to be tolerant to ischemia and reperfusion.

Primary liposarcoma of the mediastinum —A case report and review of the literature—

Liposarcoma of the mediastinum is a rare disease. A 59 year old woman was seen with the complaint of dizziness. A chest radiogram taken during the course of investigation for hypertension revealed a large mass shadow 24×18.5×12 cm located in the anterior mediastinum. The tumor of the mediastinum was diagnosed as a benign lipoma when it was first resected, but subsequently proved to be a liposarcoma when it re-appeared 2 years and 10 month later. Based on the WHO classification, the mixed type of liposarcoma was diagnosed. The salient and pathological features of mediastinal liposarcoma are reviewed and compared with those nine cases reported in Japan and fifty in North America and European countries. Treatment by simple enucleation or shelling out of the tumor should be discouraged, since this seems to be the main cause of local recurrence. Surgical wideen bloc excision is the treatment of choise.

Inhibition of Development of Abdominal Aortic Aneurysm by Glycolysis Restriction

Objective—The mechanisms underlying abdominal aortic aneurysm development remain unknown. We hypothesized that acceleration of glucose metabolism with the upregulation of glucose transporters is associated with abdominal aortic aneurysm development. Methods and Results—Enhanced accumulation of the modified glucose analogue 18 fluoro-deoxyglucose by positron emission tomography imaging in the human abdominal aortic aneurysm was associated with protein expressions of glucose transporters-1 and -3, assessed by Western blot. The magnitude of glucose transporter-3 expression was correlated with zymographic matrix metalloproteinase-9 activity. Intraperitoneal administration of glycolysis inhibitor with 2-deoxyglucose significantly attenuated the dilatation of abdominal aorta induced by periaortic application of CaCl2 in C57BL/6J male mice or reduced the aneurysmal formation in angiotensin II-infused apolipoprotein E knockout male mice. In monocytic cell line induced by phorbol 12-myristate 13-acetate or ex vivo culture obtained from human aneurysmal tissues, 2-deoxyglucose abrogated the matrix metalloproteinase-9 activity and interleukin-6 expression in these cells/tissues. Moreover, 2-deoxyglucose attenuated the survival/proliferation of monocytes and the adherence of them to vascular endothelial cells. Conclusion—This study suggests that the enhanced glycolytic activity in aortic wall contributes to the pathogenesis of aneurysm development. In addition, pharmacological intervention in glycolytic activity might be a potential therapeutic target for the disorder.