Impact of glucose tolerance status on the development of coronary artery disease among working-age men.

AIMS: To examine the impact of glucose tolerance status on the development of coronary artery disease (CAD) in working-age men in Japan. METHODS: This population-based retrospective cohort study included 111,621 men aged 31-60 years [63,558 with normal glucose tolerance (NGT); 37,126 with prediabetes; 10,937 with diabetes]. The Cox proportional-hazards regression model was used to identify variables related to the incidence of CAD. RESULTS: Multivariate analysis showed that, compared with NGT, diabetes increased the risk of CAD by 17.3 times (95% CI: 6.36-47.0) at ages 31-40 years, by 2.74 times (95% CI: 1.85-4.05) at ages 41-50 years and by 2.47 times (95% CI: 1.69-3.59) at ages 51-60 years. The HRs for CAD in men with diabetes aged 31-40 equaled that of men with NGT aged 51-60 [18.2 (7.15-46.4) and 19.4 (8.28-45.4), respectively]. CONCLUSION: The impact of diabetes on CAD was markedly greater in men aged 31-40 years compared with those aged 41-60 years.

Strength of bond to bone and cytotoxicity of sintered bodies of hydroxyapatite/zirconia composite particles.

Regarding sintered bodies of hydroxyapatite (HAP)/zirconia (PSZ) composite particles prepared by covering the surface of HAP particles with PSZ particles, their strength of the bond to bone after implanting them into an organism and their cytotoxicity were evaluated. Cytotoxicity tests were conducted by the colony formation method. Cytotoxicity was not observed in the sintered bodies of HAP/PSZ composite particles, or in sintered monolithic HAP body and sintered monolithic PSZ body. The strength of bond between a sintered body and a bone was evaluated by measuring the shear strength at the interface between them after a fixed period following implantation of a sintered body into a rabbit femur. In all cases of the sintered monolithic HAP body, and the sintered bodies of HAP/PSZ composite particles and monolithic PSZ body, when the implantation period increased, the shear strength of the sintered body/bone interface tended to increase. In particular, this tendency was very high in the case of sintered bodies of HAP/PSZ with weight ratios of 1/1.0 and 1/1.5, the shear strength for each reaching 20 MPa 12 months after implantation.

The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo.

A newly synthesized reagent, KNK437, has been found specifically to inhibit the synthesis of heat shock proteins in vitro. In this study, we investigated the effects of KNK437 on the synthesis of heat shock proteins and the induction of thermotolerance in transplantable tumors in vivo. SCC VII cells were grown in vivo and transplanted into C3H/He mice. The concentrations of KNK437 in the tumors and the sera of the mice were examined by high-performance liquid chromatography. Hsp72 synthesis was examined by Western immunoblot analysis. The response to hyperthermia was evaluated in terms of the delay in tumor growth. KNK437 had low toxicity in vivo. The concentration of KNK437 in the tumors gradually increased and reached a peak 6 h after i.p. injection. Hsp72 were synthesized 8 h after hyperthermia at 44 degrees C for 10 min, and their synthesis was inhibited by administration of KNK437 6 h before hyperthermia. At a concentration of 200 mg/kg, KNK437 alone showed no antitumor effects and did not increase the thermosensitivity of nontolerant tumors. The same dose of KNK437 enhanced the antitumor effects of fractionated heat treatment at 44 degrees C in a synergistic manner. This study strongly suggests the inhibition of thermotolerance via the inhibition of HSP72 in vivo. The inhibition of thermotolerance by KNK437 may help to improve the efficacy of clinical fractionated hyperthermia.

Patterns of care study of radiation therapy for cervix cancer in Japan: the influence of the stratification of institution on the process.

BACKGROUND: To improve the quality of radiation oncology in Japan, Patterns of Care Study (PCS), a widely known quality assurance (QA) program in the USA, was introduced. The feasibility was tested by collecting nationwide data by extramural audit for cervix cancer. METHODS: From July 1996 through February 1997, PCS audits were performed for 29 institutions nationwide. On the basis of the facility survey by Tsunemoto, 13 institutions were classified as A1 (university hospital/cancer center), 10 as B1 (other institutions treating >120 patients/year) and six as B2 (other institutions treating <120 patients/year). Medical charts for the patients treated for cervix cancer between 1992 and 1994 were reviewed based on the data format of the US PCS. The total number of patients surveyed was 432. RESULTS: Simulation was used for >90% of the patients in both A1 and B1-2 institutions. However, in B1-2, planning for 5% of the patients was performed with only a clinical set-up (p = 0.0287). A daily fraction with a size of 200 cGy was given to >65% of patients in A1 and to <47% in B1-2. On the other hand, >50% of those in B1-2 were treated with daily fractions of 180 cGy and less compared with 25% in A1 institutions (p < 0.0001). Brachytherapy was utilized more frequently for patients in Stages II (p = 0.0365), III (p = 0.0015) and IV (p = 0.0483) in A1 than in B1-2. As for external beam equipment, linear accelerators with 10 MV or more were used for 83% of the patients in A1. However, in B1-2 institutions, machines with lower energy were used for 38% of the patients (p < 0.0001). The median number of full-time-equivalent (FTE) radiation oncologists was 2.7 in A1, 0.65 in B1 and 0.2 in B2. CONCLUSIONS: Institutional stratification, including equipment and personnel, was found to affect significantly the patterns of care for cervix cancer. Therefore, to improve the quality of radiation therapy nationwide, improvements in equipment and in supply of FTE personnel are extremely important. PCS was found to have great potential for a practical evaluation of how much improvement will be required in Japan.

Properties of cattle bone powder-coated composite particles as high-performance and open column liquid chromatographic column packings.

Cattle bone powder (CBP) from natural resources was employed as a protein adsorbent instead of chemically synthesized hydroxyapatite (HA). Though a small amount of impurities was detected, CBP possessed a crystallinity similar to HA. Using CBP/40PE prepared from CBP and polyethylene beads (40 microns) by dry impact blending as an HPLC column packing, considerable correlation was observed between the elution concentrations of proteins and their pI. Such behavior was caused by the relatively large adsorption capacity for basic proteins. CBP/40PE could completely separate gamma-globulin from BSA also as an open column chromatographic support, under relatively low concentration.

A phase I and II clinical trial of a newly developed ultrasound hyperthermia system with an improved planar transducer.

PURPOSE: The clinical usefulness of a newly developed ultrasound hyperthermia system was evaluated. METHODS AND MATERIALS: The hyperthermia system uses a modified planer transducer operated at frequencies of 0.5, 1.0, and 1.5 MHz. The transducer has a nonvibrating part at the center to reduce the central hot spot. Frequency sweeping technique is also used to eliminate the annular hot spot around the center. Thirty-eight tumors in 29 patients were examined in this study. In 35 tumors, hyperthermia was given in conjunction with irradiation and/or chemotherapy, and in the remaining 3 tumors, hyperthermia alone was given. In all, a total of 153 hyperthermia sessions were performed. RESULTS: The number of hyperthermia sessions per tumor ranged from 1 to 7 (mean, 4.0 +/- 1.3). The number of intratumor thermometry points per session ranged from 1 to 8 (mean, 4.3 +/- 1.5). The average intratumor temperature for tumors with a maximum depth of <3 cm, 3-6 cm, and >6 cm was 42.1 +/- 1.2, 41.7 +/- 1.4, and 39.9 +/- 2.0 degrees C, respectively. The percentage of monitored intratumor points with temperature exceeding 42 degrees C was 56 +/- 31%, 43 +/- 34%, and 21 +/- 24%, respectively. Of the 30 evaluable tumors treated with combined irradiation, 12 showed complete response, 14 partial response, and 4 no change. Observed complications included pain at the treatment site in 13 of the 153 treatment sessions and vesicle formation in 3 of the 38 treatment sites. No serious complication was seen. CONCLUSIONS: These results indicate that the newly developed ultrasound hyperthermia system is clinically useful for the treatment of localized superficial and subsurface tumors with a maximum tumor depth of no more than 6 cm.

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.

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%.

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.

Clinical evaluation of 430 MHz microwave hyperthermia system with lens applicator for cancer therapy.

The clinical efficacy of a microwave (MW) hyperthermia system using an electric-field converging (lens) applicator is evaluated for 42 malignant tumours with a maximum tumour depth of less than 7 cm. The mean of the maximum, average and minimum tumour temperature of the 42 tumours are 44.5, 42.5 and 40.7 C, respectively. The thermal parameters are higher for tumours in the chest, abdominal walls and hip than for those in the neck, groin and extremities. No apparent difference in thermal parameters according to the depth of tumour is shown. Of 40 tumours treated by hyperthermia in combination with radiotherapy, 20 (50%) showed complete regression, 14 (35%) showed partial regression, and six (15%) showed no change. This phase I and II study indicates clinical feasibility of the newly developed MW heating apparatus, and strongly suggests the usefulness of thermoradiotherapy in the treatment of localised superficial and subsurface malignancies.

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.

Drug dissolution from indomethacin-starch hybrid powders prepared by the dry impact blending method.

Indomethacin was hybridized with potato starch using a dry impact blending method. Resultant hybrid powders were investigated by scanning electron microscopy and X-ray powder diffraction. Amorphous indomethacin spread over the starch surface in a layer immediately after being hybridized, and then gradually reverted to fine crystalline particles adhering firmly to the starch surface. Indomethacin dissolution from the hybrid powder was compared with those from physical mixtures and granules taken from a commercially available capsule. Indomethacin dissolution from powder and capsule dosage forms, even in an acidic medium, was drastically accelerated by the hybridization.

[Current status of thermoradiotherapy in cancer therapy].

The current status of thermoradiotherapy for cancer is reviewed. The usefulness of this combined treatment for superficial tumors, in which heating and thermometry are relatively easy to apply, has been clearly demonstrated by many clinical results. With recent technological advancements, the application of thermoradiotherapy to deep-seated tumors is increasing, and encouraging results have been reported for various tumors including brain tumors, carcinomas of the breast, lung, esophagus, liver, rectum, urinary bladder, and soft tissue tumors. Thermoradiotherapy seems a very promising treatment modality for various refractory malignancies.

Quercetin, an inhibitor of heat shock protein synthesis, inhibits the acquisition of thermotolerance in a human colon carcinoma cell line.

Here, we describe the effects of quercetin on the induction of thermotolerance as examined by colony forming assay in a cell line derived from human colon carcinoma (COLO320 DM). Cells became resistant to heat treatment at 45 degrees C when they were preheated at 42 degrees C for 1.5 h or at 45 degrees C for 10 min. This induction of thermotolerance was almost completely inhibited by continuous treatment with 100 microM quercetin during the first and second heating sessions, and the interval between. This effect of quercetin was demonstrated to be dose-dependent over a concentration range of 50-200 microM. Quercetin did not increase the thermosensitivity of non-tolerant cells. The presence of quercetin during the first conditioning heating was more effective in inhibiting thermotolerance than its presence during the second heating. Quercetin was also found to inhibit the acquisition of thermotolerance induced by sodium arsenite. Cycloheximide, a nonspecific inhibitor of protein synthesis, did not affect the acquisition of thermotolerance by the same cell line. Quercetin specifically inhibits the synthesis of all heat shock proteins so far reported previously, and this leads to inhibition of the induction of thermotolerance. Such inhibition of thermotolerance by quercetin may improve the efficacy of clinical fractionated hyperthermia.

[Clinical assessment of thermoradiotherapy of breast cancer and cancer of the urinary bladder].

Non-randomized clinical trials of thermoradiotherapy for breast cancer and carcinoma of the urinary bladder were reported. Thermoradiotherapy was useful for breast cancer treatment in term of (1) increased local control for locally advanced tumors and (2) possibility of reducing dose of irradiation for recurrent tumors following radiotherapy. Tumor response to thermoradiotherapy was dependent on tumor volume and maximum or minimum tumor temperature. Thermoradiotherapy was also effective as a preoperative-treatment for urinary bladder cancer. The incidence of down-staging and degeneration of tumors was significantly higher in thermoradiotherapy than in radiotherapy. These effects were temperature dependent. Patients with T 3-4 NOMO or Grade 3 tumors treated with thermoradiotherapy showed a tendency of increased survival compared with those treated with radiotherapy alone.

The coating and the encapsulation of an interactive powder mixture and its application to sustained release preparations.

Fine cohesive isoprenaline HCl particles adhered to the surface of coarser potato starch particles to form interactive mixtures. These were coated with magnesium stearate by dry mixing. To check if there was a lowering of homogeneity in the latter stage, the degree of mixing was investigated before and after adding magnesium stearate. The surface appearance of magnesium stearate-coated interactive mixtures became smoother as mixing time increased or the temperature of the powder bed during mixing was raised. Ultimately, the magnesium stearate encapsulated the particles of interactive mixture. The coated interactive mixtures improved sustained release of isoprenaline HCl over the starch mixtures alone, the effect depending on the density of the magnesium stearate. Only in encapsulated mixtures was the release rate of drug decreased as the amount of magnesium stearate increased. The release of isoprenaline HCl from the interactive mixtures followed first-order kinetics. A linear relationship existed between the first-order rate constant and the reciprocal thickness of the magnesium stearate film, indicating a diffusion-controlled system with the film having some pores.

Preparation of drug-diluent hybrid powders by dry processing.

New hybrid powders have been produced by the dry processing of six drugs (oxyphenbutazone, prednisolone, theophylline, indomethacin, phenacetin and aspirin), with potato starch used as a core material, by means of an electric mortar and a powder surface reforming system designed to produce hybrid powders. The hybrid powders obtained immediately after production differed in their structure from interactive mixtures. With the hybrid powders the drug was spread on the surface of the core particle by friction and collision that occurred in the dry process, but with interactive mixtures the drug simply adhered as intact particles to the surface of diluent particles. Scanning electron microscopy and powder X-ray diffractometry indicated that the mechanochemical phenomenon was essential for the production of the hybrid powders. With time, a shape change in the adhering drug was observed as a relaxation process took place, with recrystallization resulting from the release of accumulated energy. The change with time might depend upon the method of producing powders and the physical properties of the drug used, e.g. the smooth layer of indomethacin produced by the powder surface reforming system reverted to fine particles tightly adhering to the starch surface, though no change was observed with prednisolone.

Intestinal absorption of oyster shell electrolysate.

High voltage electric current was passed through oyster shell powder for electrolysis. The crystalline shape of oyster shell electrolysate appeared to be quite different from that of CaO or CaCO3. Higher serum calcium values were achieved by oral administration of the same amount of as oyster shell electrolysate than as calcium carbonate in vitamin D-deficient rats, suggesting a better intestinal absorption of the former than the latter. In four patients with postoperative hypoparathyroidism with reduced intestinal calcium absorption, the same amount of elementary calcium as oyster shell electrolysate was more effective than calcium carbonate in raising serum calcium in the absence of vitamin D supplement. Oyster shell electrolysate was also more effective in suppressing serum parathyroid hormone concentration than calcium carbonate in two patients with secondary hyperparathyroidism with renal failure. Calcium thus appears to be more readily absorbed from oyster shell electrolysate than from calcium carbonate through intestinal barriers produced by insufficient vitamin D action.