Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer.

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.

CT is useful for identifying patients with complicated appendicitis.

BACKGROUND AND AIMS: We often come across patients with complicated appendicitis (perforation, abscess formation, or peritonitis) and it is essential to get accurate and detailed information on these patients preoperatively. In this study, we investigated whether or not preoperative computed tomography is useful for identifying these patients. PATIENTS AND METHODS: Plain and intravenously-contrasted helical computed tomography was obtained preoperatively in 94 (75%) of 125 patients who underwent appendectomy. Twenty-eight (30%) of the 94 patients had complicated appendicitis (Compli(+) group). We compared clinical factors and computed tomography findings of the Compli(+) group with those of 66 other patients (Compli(-) group). RESULTS: There was no significant difference between the Compli(+) and Compli(-) groups in gender, white blood cell count, the present rate of an enlarged appendix, or appendicolith. Fat stranding and free fluid on computed tomography were significantly associated with complicated appendicitis by both univariate and multilogistic regression analysis. Fourteen (70%) of the 20 patients with fat stranding and free fluid on computed tomography had complicated appendicitis and only 1 (4%) of the 28 Compli(+) patients had neither fat stranding nor free fluid on computed tomography. CONCLUSION: Our study has indicated that fat stranding and free fluid on computed tomography are significant for complicated appendicitis and helical computed tomography is a powerful tool for identifying patients with complicated appendicitis preoperatively.

[Surgery for metastatic lung tumors at our department during the last ten years].

We report on 86 cases (112 operations) who underwent surgery for metastatic lung tumors at our department during the last 10 years. The study subjects comprised 53 men and 33 women, and the average age was 51 (+/- 19) years. Of the 112 metastatectomies performed, 53 were conducted by video-assisted thoracic surgery (VATS), and 59 were performed via thoracotomy. The procedures employed for metastatectomy were lobectomy (22 cases), segmentectomy (4 cases), and partial resection. wedge resection (86 cases). The primary origin of the metastatic tumors was colorectal carcinoma in 22 cases, osteosarcoma in 13 cases, renal carcinoma in 10 cases, and breast carcinoma in 6 cases. The 5-year survival rates in subjects undergoing first and second resection for pulmonary metastases were 46% and 44%. Metastatectomy was performed 1, 2, 3, 4, 5, and 7 times in 73, 7, 1, 2, 2, 1 cases, respectively. The average number and maximum diameter of the metastatic pulmonary lesions at first metastatectomy were 1.9 and 27.6 mm. Metastatectomy is performed, as a rule, by VATS at our department, because the more highly invasive thoracotomy procedure influences the activity of the cancer cells in a suspended phase in an unfavorable manner. Furthermore, we believe that to the maximum extent possible, re-metastatectomy should also be performed by VATS. The survival rates at our institution have been satisfactory, and we attribute this to our following strict indications for metastatectomy. Re-metastatectomy should always be considered, as the survival rates are as favorable as those following the first metastatectomy.

[Therapeutic strategy for a patient suffering from a peripheral pulmonary tumor in the right upper lobe and an endotracheal tumor in the carina].

A 64-year-old male, who had received successful radiotherapy for the previous laryngeal cancer, was admitted to our department for the treatment of a peripheral pulmonary tumor in the right upper lobe and an endotracheal tumor in the carina. The endotracheal biopsy of the carinal tumor demonstrated squamous cell carcinoma, though preoperative examination of the intrapulmonary tumor was unable to clarify it's pathological type. The intrapulmonary tumor required right upper lobectomy and R2 lymph node dissection as a measure against the possibility of primary lung cancer. Since the endotracheal cancer was diagnosed as an intra mucosal tumor by the preoperative computed tomography (CT) scans and the bronchoscopic examination, laser abrasion therapy to the endotracheal tumor was performed 4 days before the lobectomy of the intrapulmonary tumor. After the pulmonary operation, the intrapulmonary tumor was diagnosed as squamous cell carcinoma without lymph node metastasis, and it was suggested to be a metastatic tumor of the previous laryngeal cancer. Both radiotherapy to the carina and general chemotherapy with docetaxel hydrate and carboplatin were used as adjuvant therapies 36 days after the lobectomy. One year after the pulmonary surgery, there is no recurrence of the tumor in the lung or carina. Laser abrasion therapy to the endotracheal tumor is very useful and safe for the patient, who should then receive pulmonary resection soon after the therapy.

Effect of chronic treatment with haloperidol on vasopressin release and behavioral changes by osmotic stimulation of the supraoptic nucleus.

Chronic treatment with dopamine D2 blockers in schizophrenic patients has been proposed as one of the causes of polydipsia and water intoxication, but this conclusion is still controversial. To investigate the relationship between dopamine D2 blockers and these syndromes, we designed a behavioral and neurochemical study using hyperosmotic stimulation in the supraoptic nucleus (SON) by microdialysis after chronic treatment with haloperidol in rats. Animals were injected with haloperidol decanoate (20 mg/kg, i.m.) or sesame oil at 2-week intervals for 8 successive weeks. During the 7th week, water-intake was increased 30-60 min after the hyperosmotic stimulation in both groups, but more so in haloperidol-treated animals compared to that in the control group. Moreover, arginine vasopressin (AVP) was released by the hyperosmotic stimulation in SON, but was not significantly different between groups. In addition, striatal dopamine levels 3-4 days after the microdialysis study showed a significant decrease in the haloperidol-treated animals. These results suggest that chronic treatment with haloperidol enhances water-intake produced by hyperosmotic stimulation in the SON but does not increase AVP levels in dialysates following hyperosmotic stimulation. Thus, these symptoms may be mediated by dopaminergic systems in brain.

Close relationship of tissue plasminogen activator-plasminogen activator inhibitor-1 complex with multiple organ dysfunction syndrome investigated by means of the artificial pancreas.

BACKGROUND: Glucose tolerance (GT) has not been taken into consideration in investigations concerning relationships between coagulopathy and multiple organ dysfunction syndrome (MODS), and endothelial cell activation/endothelial cell injury (ECA/ECI) in septic patients, although coagulopathy is known to be influenced by blood glucose level. We investigated those relationships under strict blood glucose control and evaluation of GT with the glucose clamp method by means of the artificial pancreas in nine septic patients with glucose intolerance. The relationships between GT and blood stress related hormone levels (SRH) were also investigated. METHODS: The amount of metabolized glucose (M value), as the parameter of GT, was measured by the euglycemic hyperinsulinemic glucose clamp method, in which the blood glucose level was clamped at 80 mg/dl under a continuous insulin infusion rate of 1.12 mU/kg per min, using the artificial pancreas, STG-22. Multiple organ failure (MOF) score was calculated using the MOF criteria of Japanese Association for Critical Care Medicine. Regarding coagulopathy, the following parameters were used: disseminated intravascular coagulation (DIC) score (calculated from the DIC criteria of the Ministry of Health and Welfare of Japan) and the parameters used for calculating DIC score, protein-C, protein-S, plasminogen, antithrombin III (AT-III), plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator-PAI-1 (tPA-PAI-1) complex. Thrombomodulin (TM) was measured as the indicator of ECI. RESULTS: There were no significant correlations between M value and SRH, parameters indicating coagulopathy and the MOF score. The MOF score and blood TM levels were positively correlated with DIC score, thrombin-AT-III complex and tPA-PAI-1 complex, and negatively correlated with blood platelet count. CONCLUSIONS: GT was not significantly related to SRH, coagulopathy and MODS under strict blood glucose control. Hypercoagulability was closely related to MODS and ECI. Among the parameters indicating coagulopathy, tPA-PAI-1 complex, which is considered to originate from ECA, seemed to be a sensitive parameter of MODS and ECI, and might be a predictive marker of MODS. The treatment for reducing hypercoagulability and ECA/ECI were thought to be justified as one of the therapies for acutely ill septic patients.

Off-pump Coronary Artery Bypass Grafting in patients on chronic hemodialysis.

BACKGROUND: Off-pump Coronary Artery Bypass Grafting(CABG) has gained much support but has been scarcely reported in patients on chronic hemodialysis (HD). The details of CABG for such patients on chronic HD are presented. METHODS: Between January 1998 and December 1999, off-pump CABG was performed in 5 patients on chronic HD. All patients presented with unstable angina pectoris. The indication for off-pump CABG was suitable coronary anatomy (N = 5) and expected high risks associated with cardiopulmonary bypass due to reoperation (N = 1) and impaired cerebral blood flow (N = 2). The approach was median sternotomy (N = 4) and left anterior short thoracotomy (N = 1). The mean graft number was 2.0 +/- 1.0 (range, 1-3). In situ arterial grafts were mainly used: the in situ left internal thoracic artery was used in four patients, the in situ right gastroepiploic artery in two, the in situ right internal thoracic artery in two, and the saphenous vein in two patients. RESULTS: There were no deaths or complications. Nine of 10 grafts were confirmed fully patent by postoperative angiography before hospital discharge. In a mean follow-up of 17.2 months, no patients had developed recurrence of angina or any cardiac symptom. CONCLUSION: Off-pump CABG using in situ arterial grafts can be performed on patients on chronic hemodialysis subject to suitable anatomy of the target coronary arteries.

Solitary osseous hemangioma outside the spinal and craniofacial bones.

Bone hemangioma is mainly seen in the skull and spine, and rarely occurs in other bones. We report herein four cases of osseous hemangioma arising in rare sites: In two cases, on a rib; a faintly painful mass in one case located on the scapula; and progressive pain in one case located on the ischium. The tumors presented clinically as incidental lesions on radiographs. All cases had an aggressive appearance, such as defect of the cortex, a soft-tissue mass, and a sunburst-like appearance. Markedly high signal intensity on T2-weighted magnetic resonance images was a characteristic finding. Open biopsy resulted in severe blood loss, but needle biopsy was performed safely under computed tomography guidance. It is important to note that bone hemangiomas may be misdiagnosed as malignant tumors.

Epidemiology of childhood burns in the critical care medical center of Kinki University Hospital in Osaka, Japan.

The objective of the present study was to describe the characteristics of pediatric burns in order to prepare a program for the prevention of severe burn injuries in children. We conducted a retrospective study of burn victims aged 15 years or younger who were hospitalized in our Critical Care Medical Center between 1982 and 1997. There were 73 children with burn injuries hospitalized in our center during the study period. The greatest number were children 1 year old. The average % body surface area burned was 21. 5+/-20.5%. The most important causes of pediatric burns were found to be hot bath water and other hot liquids. Hot bath scalds accounted for about half of the pediatric burns occurring in all age groups, and they were often extensive. Non-bath scalds accounted for about one-third of the pediatric burns and were most frequent in children 2 years and younger. All the injuries sustained at home occurred when a family member was in the house. Similar to many reports from overseas, non-bath scalds were one of the most common causes of burns in this study; however, hot bath scalds were the most important cause. These data are being used to develop a prevention program. We also consider it necessary to educate children and their family members about the dangers of burn injuries.

[Coronary revascularization in a patient with bilateral internal carotid artery stenosis and aneurysm of brachiocephalic artery: a case report].

A 67-year-old man with a twenty-year history of effort angina was referred to our hospital. He underwent successful PTCA for the right coronary artery and diagonal branch. However, his angina recurred three months after PTCA due to restenosis and he was recommended to undergo CABG. Because he had concomitant bilateral internal carotid artery stenosis and aneurysm of the brachiocephalic artery, we chose two-staged operation strategy to avoid cerebrovascular complication during CABG. First, he underwent bilateral carotid endarterectomy (CEA), and then he underwent concomitant CABG and grafting of brachiocephalic artery 12 days after CEA. After these operations he recovered uneventfully without neurological complication.

Electro-acupuncture stimulation to a hindpaw and a hind leg produces different reflex responses in sympathoadrenal medullary function in anesthetized rats.

The effects of electro-acupuncture stimulation (EAS) of two different areas of a hindlimb with different stimulus intensities on sympathoadrenal medullary functions were examined in anesthetized artificially ventilated rats. Two needles of 160 microm diameter and about 5 mm apart were inserted about 5 mm deep into a hindpaw (Chungyang, S42) or a hind leg (Tsusanli, S36) and current of various intensities passed to excite various afferent nerve fiber groups at a repetition rate of 20 Hz and pulse duration of 0.5 ms for 30-60 s. Fiber groups of afferent nerves stimulated in a hindlimb were monitored by recording evoked action potentials from the afferents innervating the areas stimulated. The sympathoadrenal medullary functions were monitored by recording adrenal sympathetic efferent nerve activity and secretion rates of catecholamines from the adrenal medulla. EAS of a hindpaw at a stimulus strength sufficient to excite the group III and IV somatic afferent fibers produced reflex increases in both adrenal sympathetic efferent nerve activity and the secretion rate of catecholamines. EAS of a hind leg at a stimulus strength sufficient to excite the group III and IV afferent fibers produced reflex responses of either increases or decreases in sympathoadrenal medullary functions. All responses of adrenal sympathetic efferent nerve activity were lost after cutting the afferent nerves ipsilateral to the stimulated areas, indicating that the responses are the reflexes whose afferents nerve pathway is composed of hindlimb somatic nerves. It is concluded that electro-acupuncture stimulation of a hindpaw causes an excitatory reflex, while that of a hind leg causes either excitatory or inhibitory reflex of sympathoadrenal medullary functions, even if both group III and IV somatic afferent fibers are stimulated.

Preheparin serum lipoprotein lipase mass is negatively related to coronary atherosclerosis.

In preheparin serum, there exists lipoprotein lipase (LPL) mass with little activity. The clinical significance of this preheparin serum LPL mass (preheparin LPL mass) is unclear. We studied the levels of preheparin LPL mass in patients with coronary atherosclerosis, comparing the results with those in healthy men. We also evaluated the correlation between preheparin LPL mass and the severity of coronary atherosclerosis by comparing with other risk factors such as age, smoking, family history, hypertension, hyperuricemia, diabetes mellitus, total cholesterol, triglyceride, high density lipoprotein-cholesterol and body mass index. The subjects, 70 men presenting with symptoms of coronary artery disease, underwent coronary angiographic examination. Significant narrowness was defined as > or = 75%. Control group comprised 77 men who had annual health checks and showed no abnormal findings. Preheparin LPL mass in the stenosis group was lower than normal coronary group and also than the control group. Multivariate analysis showed that preheparin LPL mass had the highest t-value (-2.53) for the number of lesions among the risk factors listed above. These results suggest that low preheparin LPL mass may be deeply involved in the progression of coronary atherosclerosis.

Angioscopic evaluation of stabilizing effects of bezafibrate on coronary plaques in patients with coronary artery disease.

Background Since long-term administrations of anti-hyperlipidemic agents result in reduction in % stenosis or increase in minimum lumen diameter (MLD) of stenotic coronary segments, it is generally believed that anti-hyperlipidemic agents stabilize vulnerable coronary plaques. However, recent pathologic and angioscopic studies revealed that vulnerability of coronary plaques is not related to severity of stenosis and the rims rather than top of the plaques disrupt, and therefore, angiography is not adequate for evaluation of vulnerability.Angioscopy enables macroscopic pathological evaluation of the coronary plaques. Therefore, we carried out a prospective angioscopic open trial for evaluation of the stabilizing effects of bezafibrate on coronary plaques.Methods From April, 1997 to December, 1998, 24 patients underwent coronary angioscopy of the plaques in the non-targeted vessels during coronary interventions and 6 months later. The patients were divided into control (10 patients, 14 plaques) and bezafibrat (14 patients, 21 plaques) groups. Oral administration of bezafibrate (Bezatol SR, 400mg/day) was started immediately after the interventions and was continued for 6 months. The vulnerability score was determined based on angioscopic characteristics of plaques and it was compared before and 6 months later.Results Six months later, vulnerability score was reduced (from 1.6 to 0.8;p < 0.05) in bezafibrate group and unchanged (from 1.4 to 1.3; NS) in control group. In bezafibrate group, the changes in vulnerability score was not correlated with those in % stenosis or MLD. Conclusion The results indicate that bezafibrate can stabilize coronary plaques.

Percutaneous dye image cardioscopy for detection of endocardial lesions.

Endocardial lesions are caused not only by inflammatory processes but also by myocardial ischemia, resulting in endocardial thrombosis and cerebral embolism. We deviced a method for direct visualization of endocardial damages by a novel dye image cardioscopy with Evans blue and examined its feasibility in patients with heart disease. The dye was injected into the left ventricle before and after endomyocardial biopsy. Endocardial surface was stained in dark blue in 63% of patients with angina pectoris before biopsy. After biopsy, the biopsied portions were stained in blue in all. The results indicate that endocardium is damaged even in apparently intact LV in patients with ischemic heart disease and that endomyocardial biopsy causes severe endocardial damages.

[Clinical study of six thymic carcinomas including long-term survivors].

Six cases of thymic carcinoma (mean age 48.5 years old, one male and 5 females) were treated in our hospital from September 1990 to September 1998. The histological subtypes of thymic carcinoma were squamous cell in 4, undifferentiated in one, and small cell in one. All cases underwent midsternal thoracotomy, 4 had total resection of the tumor and 2 had exploratory thoracotomy due to tumor invasion of the aorta and the main pulmonary artery. Within 2 years after operation, 2 cases without radiation therapy were died of the carcinoma and one case was died of asthma. However, two cases of squamous cell carcinoma have been alive and disease free for 3 and 5 years since the operation followed by mediastinal irradiation. We think that radiation therapy is very effective to control the disease because one of them underwent only exploratory operation prior to irradiation. Another one case who survives 5 years after total resection of the tumor following irradiation revealed swelling of numerous mediastinal lymph nodes, pathologically consisted of non-caseating epithelioid cell granulomas without metastasis of carcinoma, at the time of operation. These lymph nodes were diagnosed as "sarcoid-like reaction" because there was no clinical evidence of generalized sarcoidosis. The "sarcoid-like reaction" may contribute to the 5-year survival of the patient because it is thought to be a local immune response against the cancer cells. A remaining patient, alive 6 months after total resection of the thymic small cell carcinoma following irradiation, received preoperatively three cycles of the intra-arterial administration using CBDCA via bilateral internal mammary arteries. This induction chemotherapy had no response of the tumor size, but it was considered to have a possibility of reducing the size of thymic carcinoma by the use of other agents (CDDP, VDS etc.) because the tumor was fed mainly by the highly developed internal mammary arteries.

The effect of electro-acupuncture stimulation on the muscle blood flow of the hindlimb in anesthetized rats.

The effect of electro-acupuncture stimulation (EAS) on blood flow in the muscle biceps femoris (MBF) and on mean arterial pressure (MAP) was investigated in anesthetized, artificially ventilated rats. EAS was applied to a hindpaw for 30 s at intensities of 0.1-10.0 mA and at frequencies of 1-20 Hz, and MBF was measured by laser Doppler flowmetry. EAS at less than 1.0 mA, which excited group II fibers maximally and III fibers partially in a saphenous nerve, had no significant effect on MBF or MAP, although both revealed variable responses. EAS at 1.5 mA, which additionally excited group III fibers almost maximally and was subthreshold for group IV fibers, produced a small but significant increase in MBF and MAP. These responses were further increased at 2.0 mA or more, which was suprathreshold for group IV fibers. The increased response of MBF at 10.0 mA was followed by a small decrease in MBF. EAS at 1.5 mA or more also elicited a decrease in renal blood flow (RBF) and an arterial pressor response. Following severance of the bilateral splanchnic nerves, EAS at 10.0 mA induced only a slight increase in MAP and a decrease in MBF. The decrease in MBF was abolished following further severance of the bilateral lumbar sympathetic trunks (LSTs). In conclusion, EAS to a hindpaw at a stimulus strength sufficient to excite group III and IV afferent fibers, particularly group IV afferent fibers, can produce a reflex decrease in MBF via a reflex activation of muscle sympathetic activity, although this decrease in MBF is overridden by an increase in MBF caused passively by a reflex MAP pressor response elicited by a reflex increase, at least in splanchnic sympathetic activity.

Cutaneous afferents producing a reflex pupil dilation in anesthetized rats.

Cutaneous afferents producing a reflex pupil dilation were examined using natural mechanical stimulation of the hindlimb skin and electrical stimulation of a sural nerve in anesthetized, artificially ventilated rats. Pupil diameter was continuously recorded after magnification using a microscope connected to a charge coupled device camera. Innocuous brushing, or weak pressing of the skin, did not have any effect on pupil diameter, while pressing the skin more than 720 g/cm2 produced a pressure-dependent pupil dilation. Pinching rather than pressing the skin induced the larger pupil dilation. Electrical stimulation of a sural afferent nerve with weak intensity, which was supra-threshold for Abeta-afferents and sub-threshold for Asigma-afferents, induced a reflex pupil dilation. This dilation continued to increase with further increases in stimulus intensity which involved excitation of Asigma afferents and C afferents. It is concluded that Abeta, Asigma and C afferents in the skin can work as afferents in eliciting reflex pupil dilation in anesthetized rats.

Interlaboratory validation of the in vitro eye irritation tests for cosmetic ingredients. (5) Skin(2TM) ZK1100 and tissue equivalent assay.

Skin(2TM) ZK1100 (ZK1100) assay and tissue equivalent assay (TEA, Skin(2TM) ZK1200) are human dermal models. These assays were evaluated as alternatives to the Draize eye irritation test (Draize test) in rabbits. Thirty-nine cosmetic ingredients were selected and used as test substances. The ZK1100 assay was conducted according to an original protocol provided by Advanced Tissue Sciences, a kit supplier. The TEA assay followed a protocol developed by Osborne et al., (1995a). Coefficients of variation (CV) ranged from 11.7 to 133 in results from the ZK1100 assay; three test substances showed the CVs more than 100. These were cetyltrimethylammonium chloride (S3-7), domiphen bromide (S3-11) and di(2-ethylhexyl) sodium sulfosuccinate (S3-14). Acid Red 92 (S2-3) was excluded from data analysis because its absorbance interfered with the endpoint of ZK1100 assay. The CVs from the TEA assay ranged from 31.8 to 119; two test substances showed the CVs more than 100. These were acetic acid and glycolic acid (S3-13). Butanol (S3-9) was excluded from the analysis because it was assumed to volatilize during a sample preparation. Pearson's coefficient of correlation with maximum average Draize total score (MAS) and 24hr score from the Draize tests were -0.71 and -0.72 for the ZK1100 results and -0.63 and -0.60 for the TEA results. When a MAS of 15 was set as a breakpoint for the classification of eye irritancy on Cooper's plots comparing the in vitro and the Draize data, the ZK1100 results showed five false positives and four false negatives; the TEA results showed three false positives and no false negatives.