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Biomedical subjects

Y Nishimura

Publications and source records attributed to Y Nishimura.

At least 1,333 records · Page 74Linked to original sources
PubMedDate not supplied

The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours.

It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.

Animals↗
PubMedDate not supplied

Induction of vascular endothelial growth factor (VEGF) by hyperthermia and/or an angiogenesis inhibitor.

Intratumoral localization of vascular endothelial growth factor (VEGF) following administration of hyperthermia (HT) and/or anti-angiogenic drugs (TNP-470) was evaluated using SCC VII tumours in C3H/He mice. Hyperthermia at 44.0 degrees C for 30 min was given with a water bath on day 0. TNP-470 (100 mg/kg) was administered alone or after HT on day 0 and day 3. Histological changes on day 4 were evaluated by haematoxylin-eosin (HE) staining and immunohistochemical staining for VEGF. The percentage of the necrotic area relative to the entire tumour area (the % necrotic area) was measured on HE stains. The average % necrotic area of the untreated SCC VII tumours was 7%, while those of tumours treated with TNP-470 alone and HT alone were 27 or 65%, respectively. When HT and TNP-470 were combined, the % necrotic area was 82%, which was significantly higher than that caused by HT alone (p < 0.05). Immunohistochemical staining for VEGF in untreated SCC VII tumours was weak, although strong staining for VEGF was noted in untreated EMT-6 tumours of BALB/c mice, which have spontaneous central necrosis. After administration of HT and/or TNP-470, layer-shaped staining by VEGF was observed in the residual SCC VII tumour cells adjacent to the necrotic area. In conclusion, the expression of VEGF increased in response to administration of HT and/or TNP-470. Hypoxia caused by heat-induced vascular damage may be attributable to increased expression of VEGF in SCC VII tumours.

Animals↗
PubMedDate not supplied

For the clinical application of thermochemotherapy given at mild temperatures.

It has been demonstrated in vitro and in vivo that hyperthermia can enhance the cytotoxicity of some chemotherapeutic agents. This paper summarizes the authors' own laboratory studies on the effect of chemotherapeutic agents given at elevated temperatures, experimental results obtained using animal tumour systems in other laboratories, and clinical trials of thermochemotherapy reported in literature. The in vivo studies have demonstrated that the thermal enhancement of cytotoxicity of many chemotherapeutic agents is maximized at mild temperatures such as at 40.5-43 degrees C. Comparison of in vitro and in vivo results using five agents show that the in vivo thermal enhancement increases with an increase in the activation energy obtained in the temperature range between 40.5 and 43.0 degrees C. A summary of experimental results obtained by various investigators indicates a potentially wide variation in the thermal enhancement of a given agent among the different types of tumours and suggests potential agents useful at moderately elevated temperatures. In vivo studies on nine different agents indicate that the drug(s) of choice at physiological temperatures may not be the drug(s) of choice at elevated temperatures. It is also shown that drug concentration in the target must be high for sufficient thermal enhancement. Clinical trials of thermochemotherapy have employed various heating methods, including local heating, hyerthermic perfusion and whole body hyperthermia. Extensive trials have been made in the treatment of melanoma and soft tissue sarcoma in the extremity. Hyperthermic isolated perfusion with chemotherapeutic(s) provides much higher drug concentration than a systemic drug administration in the target(s), resulting in a high tumour response rate and an increased survival of the patients. It is of interest that the most successful agent used in the treatment of both melanomas and sarcomas is melphalan and is the drug of choice at moderately elevated temperatures among the nine agents tested in the in vivo studies. Current results using the tumour necrosis factor with melphalan are impressive. In several institutes, techniques have been developed to uniformly heat the localized tumour, but studies are needed to find an agent effective at elevated temperatures to each type of tumours and to establish the methods for obtaining a sufficient drug concentration in the target tissue.

Animals↗
PubMedDate not supplied

Clear cell adenocarcinoma of the endometrium is a biologically distinct entity from endometrioid adenocarcinoma.

Clear cell adenocarcinoma (CCA) of the endometrium has a poor prognosis, although the biologic features of this rare tumor are not clear. In this study, we analyzed the expression of biologic markers relating to carcinogenesis, tumor growth, and progression. Thirteen cases of CCA were compared with cases of endometrioid adenocarcinoma (EMA) of the endometrium. Immunohistochemical staining for p53; Ki-67; cyclins A, D1, and E; E-cadherin; progesterone receptor (PR)-A and PR-B; P-glycoprotein; MLH1; and MSH2 was performed. Labeling indices of p53, Ki-67, and cyclins A, D1, and E in CCA were 46.4 +/- 24.3%, 52.1 +/- 20.5%, 37.9 +/- 21.4%, 12.3 +/- 27.9%, and 8.2 +/- 22.9%, respectively. E-cadherin was expressed in only 1 case (7.7%) of CCA, as compared to 39 cases (61.0%) of EMA. No CCAs were positive for PR-A and PR-B. P-glycoprotein was detected in seven cases (53.8%). Loss of either MLH1 or MSH2 expression occurred in eight cases (61.5%). High-level expression of p53, cyclin A, and P-glycoprotein, and low-level or no expression of cyclin E, E-cadherin, PR-A, and PR-B was observed in CCA compared with EMA. The mechanism of cell-cycle regulation in endometrial CCA is different from that in EMA and may influence its malignant potential. Endometrial CCA is a distinct entity from EMA.

Adenocarcinoma, Clear Cell↗
PubMedDate not supplied

Absence of bundle structure in the neocortex of the reeler mouse at the embryonic stage. Studies by scanning electron microscopic fractography.

The reeler mutant mouse is characterized by a derangement of the cerebral cortical structure due to abnormalities during the migration step at the embryonic stage. We have analyzed both the control and reeler cerebral cortex by means of scanning electron microscopic fractography. In the control cerebral cortex, the bundle formation was composed of fine fibers on which the migrating neuroblasts were attached perpendicular to the pial surface, whereas no bundle formation was observed in the reeler; instead, there was a fine meshwork of fibers surrounding the neuroblasts. The possible role of bundle formation in the normal cerebral cortex and the correlation between the inability of cells to migrate and the absence of bundle formation in the reeler is discussed.

Animals↗
PubMedDate not supplied

Cerebral and cerebellar blood flow autoregulations in acutely induced cerebral ischemia in spontaneously hypertensive rats--transtentorial remote effect.

Autoregulation of cerebral (CBF) and cerebellar blood flow (CeBF) was studied before, during and after acutely induced cerebral ischemia in spontaneously hypertensive rats. Cerebral ischemia of the supratentorial portion was induced for one hour by bilateral carotid artery ligation (BCL). The animals were artificially ventilated and the blood flow was measured with a hydrogen clearance technique. To test the autoregulation, the blood pressure was stepwise lowered by bleeding and maintained at a new level, i.e. 15% or 30% lower than the baseline values before, during and after cerebral ischemia. At the preischemic state, CBF and CeBF were 52.1 +/- 6.2 and 58.9 +/- 4.6 ml/100 g/min (mean +/- SEM), of which autoregulations were normally preserved. Following BCL, CBF was markedly decreased to about 10% of control value while CeBF was minimally reduced to 46.9 +/- 8.6 ml/100 g/min (80%). At the ischemic state, CBF became almost zero flow during hypotension. CeBF was also reduced to 74% and further to 58% of the resting value by 15% and 30% decrease in the blood pressure, respectively, indicating impaired CeBF autoregulation. At the 30 min post-ischemic state, CBF was recovered to 48.0 +/- 4.9 and CeBF to 53.9 +/- 5.4 ml/100 g/min. Autoregulation of CBF was still abolished, whereas CeBF was kept constant by 15% fall of blood pressure and slightly reduced to 84% by 30% hypotension, indicating almost recovery of CeBF autoregulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Reduced function of CD4+25+ regulatory T cell fraction in silicosis patients.

The quality and quantity of CD4+25+ regulatory T cells (Treg) in silicosis patients (SIL) were examined and compared with results from healthy donors (HD) because SIL often develop autoimmune diseases along with pulmonary disorders. Peripheral blood mononuclear cells from 57 SIL and 50 HD were analyzed for Treg. Treg frequency and clinical parameters were subjected to a factor analysis. Treg and CD4+25- T cells (Tneg) from five HD and five SIL, sorted by flow-cytometer, were used for functional assays of Treg, the expression pattern of Treg specific genes (FoxP3, GITR and CTLA-4) and activation-related genes (CD122 and CD123). Although the actual frequency of Treg did not differ between SIL and HD, the age-corrected level was reduced in SIL. The factor analysis showed that Treg frequency was positively associated with the serum level of IL-2. The inhibitory effect of Treg on Tneg activation was decreased when the Treg:Tneg ratio was 1:1/4 to 1/2. In addition, Treg dominancy of FoxP3 and CTLA-4 expression and Tneg dominancy of CD132 expression found in HD were lost in SIL. These results indicated that the Treg fraction in SIL may be substituted with chronically activated T cells due to recurrent exposure to silica, resulting in a reduction in the frequency and function of Treg. Since the reduction of Treg may precede the clinical manifestation, as silicosis may be a pre-clinical status for autoimmune diseases, control of Treg function using cell and/or gene therapy may be a good way to manage autoimmune disease.

Aged↗
PubMedDate not supplied

Expression of the T cell receptor Vbeta repertoire in a human T cell resistant to asbestos-induced apoptosis and peripheral blood T cells from patients with silica and asbestos-related diseases.

To explore the effects of asbestos and silica on the human immune system, an experimental model of low-dose and long-term exposure was established using a human HTLV-1-immortalized polyclonal T cell line, MT-2 (MT-2Org). MT-2 cells were continuously exposed to asbestos at a concentration (10 microg/ml) which does not induce complete cell death during short-term exposure. After acquiring resistance to CB-induced apoptosis (designated MT-2Rst), an immunological comparison was made between the MT-2Org and MT-2Rst lines in terms of T cell receptor-Vbeta (TcR-Vbeta) expression. MT-2Rst cells showed excess expression of various TcR-Vbeta, although TcR-Vbeta-overpresenting cells were characterized as undergoing apoptosis due to first contact with CB. Patients with asbestos-related diseases (ARD), such as asbestosis and malignant mesothelioma, were compared with silicosis (SIL) patients as a disease control and with healthy donors (HD). SIL and ARD not only differed in their causative materials, silica and asbestos as mineral silicates, but also in terms of complications; autoimmune disorders in SIL and tumors in ARD. ARD patients showed a restricted overpresentation of TcR-Vbeta without clonal expansion, whereas SIL patients revealed significant overpresentation of TcR-Vbeta 7.2. These experimental and clinical analyses indicate the superantigenic and dysregulation of autoimmunity-inducing effects of asbestos and silica, respectively.

Adult↗
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Electromagnetic fields inhibit endothelin-1 production stimulated by thrombin in endothelial cells.

Electromagnetic field (EMF) radiation has been found to induce arteriolar dilatation, but the mechanism of action remains largely unknown. This study investigated the effect of EMF radiation on the production of endothelin-1 (ET-1), a potent vasoconstrictor, by cultured endothelial cells. EMF radiation reduced ET-1 basal levels in human umbilical vein and microvascular endothelial cells, but failed to reduce ET-1 basal levels in bovine and human aortic endothelial cells. EMF radiation significantly inhibited thrombin-stimulated ET-1 production in all four endothelial cell types in a dose-dependent manner. EMF radiation significantly inhibited thrombin-induced endothelin-1 mRNA expression in all four cell types. The inhibitory effect of EMF radiation on ET-1 production was abolished by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (10(-3) mol/1). These results demonstrate that EMF radiation modulates ET-1 production in cultured vascular endothelial cells and the inhibitory effect of EMF radiation is, at least partly, mediated through a nitric oxide-related pathway.

Animals↗
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Clinical results of thermoradiotherapy for locally advanced and/or recurrent breast cancer--comparison of results with radiotherapy alone.

From August 1979 until 1988, 26 breast cancer patients with 30 tumours were treated by hyperthermia in combination with radiotherapy. Of the 30 tumours, 11 were locally advanced primary tumours (group 1), six were locally advanced recurrent tumours after operation (group 2) and 13 were locally recurrent tumours after radiotherapy (group 3). The thermal profiles showed that the capability of an RF capacitive heating device is comparatively high for large breast tumours with a volume of more than 100 cm3, and that of a 430 MHz microwave device with a single-lens applicator is excellent for localized tumours. The response rate of group 1 and 2 tumours was excellent, and superior to that of historically controlled tumours that were treated by radiotherapy alone from July 1962 until August 1979. In group 3 the tumour response to thermoradiotherapy was not different from that to radiotherapy, but the possibility of significantly reducing total irradiation dose was indicated. More than one good heating session led to a significantly high local response, and factors having a tendency to influence local response were average minimum tumour temperature, tumour volume, and number of effective heat treatments.

Adult↗
PubMedDate not supplied

Clinical research into hyperthermia treatment of cancer using a 430 MHz microwave heating system with a lens applicator.

Tokyo Metropolitan Komagome Hospital, Kyoto University Hospital, and Aichi Cancer Center used a lens applicator microwave equipment, the HTS-100, to treat 90 patients with a total of 96 tumours. The results were analysed, and the following conclusions reached. Three clinical cases have been presented to illustrate the features of the HTS-100. (1) The results of 383 heating sessions using the HTS-100 were analysed. Even tumours larger and deeper than 5 cm could be heated above 42 degrees C. The heating area is much wider than that of the other 2450, 915, 430 MHz microwave heating equipments. (2) Hyperthermia treatment using the HTS-100 was combined with radiotherapy. The percentage effectiveness in terms of CR+PRa was 66.3% for the 89 cases which could be evaluated. Even for tumours larger than 5 cm, and deeper than 4 cm, local control was achieved in 60.7%. Thus, the indications for microwave heating have been significantly expanded. (3) Combination of microwave heating and RF heating is a new protocol which also expands the indications for hyperthermia therapy. (4) The percentage of patients experiencing the side-effects of pain, a sensation of heat, and burns was 15.6%, 6.3%, and 3.6%, respectively. Most of these side-effects were mild and temporary. The percentage of patients experiencing pain was higher than in conventional microwave heating, probably because the area of heating was wider. (5) In the future, the HTS-100 can be expected to play an important role in clinical cancer hyperthermia.

Adolescent↗
PubMedDate not supplied

Phase I/II trial of preoperative thermoradiotherapy in the treatment of urinary bladder cancer.

Between April 1984 and September 1988, preoperative radiotherapy or thermoradiotherapy was administered to 49 patients with bladder cancer (T1-4N0M0; UICC classification, 1987). Twenty-one patients were preoperatively treated by radiotherapy alone, with 4 Gy per fraction and three fractions per week to a total dose of 24 Gy (TDF = 53, group 1). The other 28 patients were treated by the same radiotherapy regimen in combination with hyperthermia (group 2). Regional hyperthermia was administered for 35-60 min immediately after irradiation (two sessions per week to a total of four sessions) using an 8 MHz RF capacitive heating device. Group 2 was divided into group 2 (high), in which the average intravesical temperature (T(av)) was > 41.5 degrees C, which was the mean value, and group 2 (low) with a T(av) < 41 x 5 degrees C. Group 2 (high) showed a significantly higher incidence of down-staging and tumour degeneration than both group 1 and group 2 (low). In addition, the local recurrence rate was lower and survival time was longer in group 2 than in group 1, although not significantly so. In particular, the patients with T3-4 or grade 3 bladder cancer in group 2 had a longer average survival than those in group 1, although the difference was not significant. The toxicity associated with hyperthermia was pain during treatment, and complications were not serious.

Adult↗
PubMedDate not supplied

Site-specific phase I, II trials of hyperthermia at Kyoto University.

Site-specific phase I, II trials of locoregional hyperthermia undertaken at Kyoto University are briefly reviewed. Thermometry analysis demonstrated the usefulness of RF (radiofrequency) capacitive heating equipment in the treatment of various subsurface or deep-seated tumours including locally advanced breast cancers, soft tissue tumours, lung cancers involving the chest wall, liver tumours, unresectable or recurrent colorectal cancers, and invasive urinary bladder cancers. The difficulty in heating whole tumour volume or hypervascular tumours to therapeutic temperatures was also shown. Non-randomized trials for locally advanced breast cancers, unresectable or recurrent colorectal cancers and invasive urinary bladder cancers demonstrated a higher response rate in thermoradiotherapy than in radiotherapy alone. The complications associated with treatment were not generally serious except for chronic bowel damages in a trial for colorectal cancers. These promising phase I, II trials encourage the future phase III trials.

Breast Neoplasms↗
PubMedDate not supplied

Development of intra-arterial hyperthermia using a dextran-magnetite complex.

Dextran-magnetite complex (DM) is a colloidal sol of subdomain magnetite particles (i.e. a 'magnetic fluid'). The specific absorption rate of DM in an AC magnetic field is much higher than those of multidomain ferrite particles due to its different mechanism of heat generation. We designed two DM-containing embolic materials (a DM/Lipiodol emulsion and a DM/degradable starch microsphere suspension) to heat target tissues with the use of an external AC magnetic field. In vitro experiments showed that the heat-generating capacity of DM was not reduced in these mixtures. When these materials were injected into the renal arteries of Japanese white rabbits, they both achieved embolization of the artery and selective heating of the embolized kidney by exposure to a 100 kHz AC magnetic field of approximately 15,000 A/m. Histological examination showed a homogeneous distribution of DM in the embolized kidney. These results suggest the possibility of using DM-containing embolic materials for inductive hyperthermia.

Animals↗
PubMedDate not supplied

Clinical results of thermoradiotherapy for soft tissue tumours.

Thirty-one unresectable and/or recurrent soft tissue tumours in 27 patients underwent hyperthermia in combination with radiation therapy. Locoregional hyperthermia was administered once or twice a week for 40-60 min to a total of 2-14 sessions using RF capacitive or microwave heating equipment. Radiation therapy was given 10-20 min before hyperthermia at doses of 20.8 to 70 Gy. The mean +/- SD of the maximum, average, and minimum intratumour temperatures was 44.0 +/- 2.9 degrees C, 42.3 +/- 1.6 degrees C, 40.1 +/- 1.1 degree C respectively, and that of the percentage of the intratumour points that exceeded 41 and 43 degrees C was 66.0 +/- 33.6, and 31.0 +/- 26.1 respectively. Of the 31 tumours treated, 13 (42%) showed CR (complete regression), 10 (32%) PR (> 50 and < 100% regression) and 8 (26%) NC (< 50% regression). Since intratumour low density areas on post-treatment CT scans have been demonstrated to be a useful parameter for assessing tumour response to thermoradiotherapy, the presence of low density areas was also assessed. Low density areas were classified into the following three categories according to the percent area occupied in the maximal cross-section of the tumour: type I, < 50%, type II, 50-80%; type III, > 80%. Of 20 tumours evaluable, 6 (30%) exhibited type III change, 11 (55%) type II and 3 (15%) type I. All of the type III tumours demonstrated a marked response on follow-up or histopathological examination. The major complication associated with treatment was skin ulcer in two patients. The five-year survival of the total 27 patients and 18 patients who had no distant metastases at the start of treatment was 32 and 48% respectively. These results indicate the clinical benefit of thermoradiotherapy using RF capacitive or microwave equipment for locally advanced and/or recurrent soft tissue tumours.

Adult↗
PubMedDate not supplied

Clinical experiences in the thermoradiotherapy for advanced gastric cancer.

Recurrent and/or inoperable gastric cancer has been treated by thermoradiotherapy at Kyoto University Hospital since 1983. In the present study, the efficacy of hyperthermia (using radiofrequency capacitive heating) plus radiotherapy for gastric cancer was evaluated in 21 patients with local recurrence, abdominal wall metastases, peritonitis carcinomatosis or paraaortic node metastases. The intratumour temperature was measured using a microthermocouple thermometer. The means of the maximum, average, and minimum intratumour temperature were 43.5, 42.1, and 41.1 degrees C respectively. The local tumour response was evaluated using computed tomography (CT). The local response rate (complete regression plus partial regression/all tumours) was 88.9%, which seemed to be higher than that of other reports using thermochemotherapy or radiotherapy alone. The one-year cumulative survival rate was 39.1%.

Adult↗
PubMedDate not supplied

Thermoradiotherapy of superficial and subsurface tumours: analysis of thermal parameters and tumour response.

Between 1988 and 1993, 57 superficial and subsurface tumours of various tumour type were treated with a 430-MHz microwave heating device. Mean (range) tumour depth of the 57 tumours was 3.0 (0.5-6.5) cm. Fifty-four tumours were treated with thermoradiotherapy. Total radiation dose ranged from 20 to 70 Gy with a mean of 53 Gy. For the remaining three tumours, thermochemotherapy was performed. Hyperthermia was given once a week, and a total of 207 heat sessions was administered. Our goal of hyperthermia treatment was to elevate all monitored tumour points > 41 degrees C for > 30 min. The mean (range) number of intratumoral thermometry points was 3.7 (2-6). The goal of hyperthermia treatment was achieved in 49% of the sessions. At the time of maximum tumour regression, complete response was noted in 53% of the tumours treated with thermoradiotherapy. Univariate analysis demonstrated that parameters including tumour type (breast cancer versus others), tumour depth, minimum tumour temperature, average tumour temperature, minimum equivalent time at 43 degrees C, and number of heat sessions achieving the treatment goal significantly affected the tumour response of the combined treatment, while total radiation dose and number of heat sessions were not significant factors for tumour response. Multivariate logistic analysis revealed that only tumour depth (< 3 versus > or = 3 cm) was a significant prognostic factor for tumour response (p = 0.029). Tumour type (breast cancer versus others) and a number of heat sessions achieving the treatment goal (0-1 versus 2-5) were found to be of borderline significance in the multivariate analysis (p = 0.075 and 0.097 respectively). The number of heat sessions achieving a minimum tumour temperature of > 41 degrees C for > 30 min seems a practical thermal parameter that influences tumour response. The present study indicates the importance of quality and quantity of heat session on the treatment outcome of thermoradiotherapy.

Adolescent↗