Biomedical subjects
Publications and source records attributed to M Nishio.
We report two patients with esophageal cancer who responded to UFT. The patients were a 71-year-old female and a 61-year-old male, both of whom had recurrent disease in the esophagus or abdominal lymph nodes. They had received previous treatment consisting of radiotherapy and chemotherapy containing cisplatin, methotrexate and peplomycin. Each patient was administered UFT 400 mg/day p.o. No toxic effect was seen.
Between 1974 and 1982, 78 primary esophageal squamous cell carcinomas were treated by external irradiation combined with additional intracavitary radium therapy. 50 to 60 Gy were given by external irradiation, and 5 to 20 Gy were delivered on the surface of the esophageal mucosa. The combined dose ranged from TDF 110 to 140 on the esophageal mucosa and TDF 95 to 120 at a depth of 5 mm from the esophageal mucosa. The 5-year survival rate was 19.3% by this combined radiotherapy alone. We conclude that the optimal dose of the combined therapy for esophageal cancer ranges from TDF 95 to 120 at a depth of 5 mm from the esophageal mucosa.
Brachytherapy is one of most effective methods of radiotherapy for cancer, and therefore, low-dose-rate brachytherapy is widely used for carcinoma of the uterus and carcinoma of the tongue. Between 1974 and 1983, 76 primary thoracic esophageal squamous cell carcinomas were treated with external irradiation combined with additional intracavitary radium therapy at the National Sapporo Hospital. The esophageal primary control rate was 34% and the 5-year survival rate was 24.1%. We believe that external irradiation therapy followed by additional intracavitary radium irradiation produces good results. Also, from 1982, 30 patients with small residual or unresectable tumors received interstitial irradiation using an after-loading technique and iridium-192 seeds. Eighteen of these 30 patients treated with iridium-192 were recurrent cases, and 20 had outer tubes intra-operatively inserted into the tumor following iridium-192 irradiation. Ten of these patients had brain tumor, nine had cancer of the head and neck, and each of the remaining fifteen had the following malignancies: lung cancer, breast cancer, pancreatic cancer, bile duct cancer, uterus cancer, skin cancer and soft tissue sarcoma. Overall 4-year survival was 17.1% in among the patients treated with Ir 192. Favorable preliminary results from these patients and those of various clinical trials on the extension of indications for brachytherapy were also reported.
In order to analyze the chronic radiation injury on the eye, 264 cases with carcinoma of the paranasal sinuses were accumulated from the four large hospitals. 50% appearance dose of the chronic radiation injury, chiefly the radiation cataract, in 3, 5, 7 and 10 years after radiotherapy was 51.6 Gy, 28.3 Gy, 23.9 Gy and 21.6 Gy, respectively.
Cooperative study from six institutes was made for the late radiation damage of oral mucosa and mandibular bone. Analysis was made for the selected patients with oropharyngeal cancer for external beam alone and with tongue cancer for interstitial implant. All of them were followed at least two years without recurrence having no secondary treatment after initial radiotherapy. As for external beam alone, frequency of the mucosal ulcer was not increased with high dose level, but tolerance dose for the oral mucosa was limited from associated mandibular damage. Late damages were not likely after brachytherapy alone.
Osteonecrosis following radiation therapy in 611 Patients with uterine cancer and 41 patients with pediatric tumor were studied. The 5- and 10-year cumulative bone injury rate after radiation therapy in uterine cancer was 4% and 15.6%, respectedly. Patients who are older than 60 years of age showed high occurrence of radiation bone injury. Otherwise, severe aletrations in shape and complete arrest of growth in irradiated growing bone were observed of even with small doses of 1600 cGy in the lower age level (0-3 age of years) at the time of treatment.
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The Ca current was isolated and the effects of ryanodine were examined in Cs-loaded guinea-pig ventricular myocytes. The time course, amplitude and voltage dependence of the Ca current were not affected by the external or internal application of ryanodine, thereby suggesting that this alkaloid has no direct action on the Ca channel and that the inactivation of the Ca channel is not affected by Ca released from sarcoplasmic reticulum, at least under the present experimental conditions.
Tetraethylammonium chloride (TEA) at concentrations over 10(-3) mol/l produced a concentration-dependent contraction in the isolated canine coronary artery. We investigated mechanisms of the contractile response and the effects of various vasodilators on the contraction. While phentolamine, propranolol, guanethidine, atropine and tetrodotoxin did not affect the TEA response, the response was attenuated by a reduction in the extracellular potassium concentration and was augmented by an increase in the concentration of potassium. The response was also augmented by other potassium conductance blockers (CsCl and 4-AP). On the other hand, the contractile response to phenylephrine used as a control drug was not affected by the extracellular potassium concentration or by CsCl. Verapamil or removal of extracellular calcium abolished the TEA, but not the phenylephrine response. Nicorandil, isoproterenol, adenosine or glyceroltrinitrate produced an equipotent relaxation in the coronary arteries contracted by TEA and by phenylephrine, whereas acetylcholine relaxed to a lesser extent the arteries contracted by TEA than those contracted by phenylephrine. These results suggest that the TEA-induced contractions are strictly dependent on the reduction of potassium conductance and extracellular calcium while the phenylephrine-induced contractions are not and that the relaxing effects of tested vasodilators, except for acetylcholine, may not be affected by such different contractile mechanisms.
Sixteen patients with advanced or recurrent squamous cell carcinoma of the esophagus were treated with cisplatin 80 mg/m2 i.v. on day 1, methotrexate 40 mg/m2 i.v. on day 2 and peplomycin 15 mg/day 24 hours continuous subcutaneous infusion from day 2 to day 5. Each course was repeated every 3 weeks. The overall response rate was 56% (9/16) with no complete response. Of 10 patients with no prior therapy, 7 (70%) showed partial response. Toxic effects were acceptable with no fatalities, but severe nausea and vomiting (56%), transient nephrotoxicity (44%), anemia (44%), thrombocytopenia (31%) and leukocytopenia (19%) occurred. No clinical evidence of pulmonary toxicity was seen. The dose-limiting toxic effect of this regimen was myelosuppression.
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Blood levels, tissue distribution and excretion of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in rats received 14C-THP or unlabeled THP at a dose of 5 mg/kg, respectively. The THP disappeared rapidly from the blood and transferred to tissues immediately after an administration. Pharmacokinetic analysis of the plasma level of THP by the simulation according to a three-compartment open model provided large values of apparent volume of distribution in the tissue compartment. The plasma half-lives of THP in alpha, beta and gamma-phases were 0.25 minute, 0.241 hour and 5.11 hours, respectively. The THP was distributed to the lung and spleen at a level about 100 times as high as the plasma level after an intravenous administration. A high level of THP was also found in the lymph node and gland tissues. Concentrations of THP in many tissues decreased to 1 microgram/g or less 24 or 72 hours after an injection of the drug, while the drug remained at higher levels in the thymus, spleen and tumor for a long time. After an injection of THP into the carotid artery, its distribution to the brain was apparent, but the level was lower after an injection to the tail vein. The amount of the drug transferred to a fetus was less than 0.2% of the dose. The major route for the excretion of THP after an intravenous administration was the fecal excretion via bile. Ratios of excretion of the radioactivity in the feces, urine and expired air were 80.3, 5.6 and 9.7% of the dose, respectively, 168 hours after an injection of 14C-THP. About 65% of the radioactivity was excreted in the bile up to 24 hours after injection but THP itself accounted for only 1/6 of the total radioactivity. About 80% of the excreted THP in the bile was in a conjugated form. Enterohepatic circulation of THP was observed mostly as metabolites or decomposed products of THP.
The accumulation of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) was studied in rats received intravenous administration of 14C-THP at a dose of 0.5 mg/kg/day for 14 consecutive days by determining blood and tissue levels and the excretion of the radioactivity. The radioactivity levels in plasma and blood cells after the multiple administration were higher than those after single administration. The half-life of the radioactivity after the multiple administration was longer in the blood cells but not in the plasma than the half-life after a single administration. Tissue levels of the radioactivity after the multiple injection were 2 to 4 times as high as the levels after a single injection except for the brain and testes in which a large accumulation of the radioactivity was observed. However, little accumulation of unlabeled THP was found in most tissues when determined by HPLC. The accumulation of radioactivity in tissues, therefore, was due to metabolites of THP. The disposition of 14C-THP was also examined in rats which had previously received unlabeled THP (0.5 mg/kg/day) for 13 days. The pretreatment did not affect the disposition of 14C-THP seriously, although the pretreatment raised tissue levels slightly and a rebound of plasma level of 14C-THP, and lowered the fecal excretion ratio. No induction of hepatic drug metabolizing enzymes was observed in rats after repeated administrations of THP for consecutive 14 days.
One hundred thirty-two patients with primary cases of squamous cell carcinoma of the tongue treated at National Sapporo Hospital from 1972 to 1982 were reviewed. Most primary sites were treated with interstitial needle implant with or without external beam irradiation. The local control rate by needle implant for the primary tongue lesions was 85.5%. That for the single plane implant was especially notable at 92.5%. The cumulative five-year survival rate was 92.8% in stage, I, 74% in stage II, 53.2% in stage III, 12.5% in stage IV and 64% overall.
Two hundred forty-six patients with the histologically proved squamous cell carcinoma of the maxillary sinus were treated at the Department of Radiology, National Sapporo Hospital, with various combined modes of surgery, irradiation and chemotherapy. Four combination modalities were used from 1966 to 1983. One hundred sixty-three (66.3%) patients were men and 83 (33.7%) were women. Five-year survival was 41.0% in T2 (16 cases), 22.3% in T3 (176 cases) and 15% in T4 (53 cases). In 72 cases treated since 1978 with tumor reduction as completely as possible, five-year survival was 43.5%. We recommand tumor reduction as complete as is possible and 40-50 Gy irradiation.
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The cortisone-resistant lymphocytes (CR lymphocytes) of mice treated with a group A streptococcus, Su strain, or Freund's complete adjuvant (FCA) were examined for their cytotoxicity on Ehrlich carcinoma cells and sarcoma-180 cells. Female mice of the ddY strain, 7-8 weeks of age, were injected subcutaneously with streptococci or FCA in emulsion, and they were killed 14 days later. To obtain CR lymphocytes, mice treated with and without agents were injected intraperitoneally with hydrocortisone acetate (125 mg/kg) 2 days before killing. Tumor cells and CR lymphocytes from thymus, spleen or mesenteric lymph node were suspended in Hanks balanced salt solution supplemented with 2% bovine albumin. The cytotoxicity of CR lymphocytes on tumor cells was examined by the Winn test: Tumor growth was observed in mice inoculated s.c. with the mixture of tumor cells (T) and CR lymphocytes (L) at a T/L ratio of 1/10 (10(6) tumor cells/mouse). The mesenteric and thymic CR lymphocytes of mice treated with streptococci or FCA were more effective than the corresponding lymphocytes of untreated mice in suppressing the tumor growth in animals given the cell mixture. This suggests that the treatment of mice with streptococci or FCA results in an enhancement in the cytotoxicity of mesenteric and thymic CR lymphocytes against the tumor cells.
Twenty-one patients with advanced or recurrent squamous cell carcinoma of the head and neck were treated with cisplatin, methotrexate and continuous subcutaneous infusion of peplomycin. The overall response rate was 62% (13/21) with 19% (4/21) complete response. The median duration of partial response was 2 months, while that of complete response was 3 months. Toxic effects were acceptable with no fatalities, but nephrotoxicity (33%), leukocytopenia (24%), thrombocytopenia (29%) and severe nausea and vomiting (76%) occurred. Pulmonary toxicity due to continuous subcutaneous infusion of peplomycin (15 mg/day, 4 days) was not seen.