Biomedical subjects
Publications and source records attributed to N Kodama.
A Japanese woman with condyloma acuminatum of the urinary bladder is presented. The condyloma acuminatum lesion was resected endoscopically and human papillomavirus 6/11 DNA was detected. After treatment, there has been no recurrence of the disease.
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Between December 1983 and August 1990 25 patients (a total of 29 carcinomas) with roentgenographically occult lung cancer were treated by PDT at National Kinki Central Hospital for Chest Diseases. A complete remission (CR) occurred in 21 carcinomas (72%). Of 19 carcinomas with tumor length of 1 cm or less, 17 ones (89.5%) achieved a CR. Of 21 carcinomas with visible tumor of the peripheral area, 17 ones (85.7%) achieved a CR. Five carcinomas relapsed from 7 to 18 months after PDT. The length of tumor and the visibility of peripheral area of tumor are important factors for CR and relapse. Fourteen patients (56%) had double, triple or quadruple cancers. Until now, 10 patients died. The main causes of death were metachronous secondary cancers and respiratory or heart failure. PDT have a potential to become an alternative to surgical resection as the primary treatment for early stage roentgenographically occult lung cancer.
Between August 1983 and March 1985, a randomized study was conducted that compared cisplatin (CDDP) (80 mg/m2 on day 1) alone with CDDP plus vindesine (VDS) (3 mg/m2 on days 1, 8, and 15) in 160 consecutive patients with inoperable non-small cell lung cancer (NSCLC). There were no complete responses. The response rate for CDDP plus VDS (22 of 77 patients, 29%) was significantly higher than that for CDDP alone (9 of 78 patients, 12%) (P less than 0.05). However, no difference existed in the median duration of response (20 weeks for CDDP plus VDS versus 20 weeks for CDDP alone) or the median survival time (45 weeks for CDDP plus VDS versus 39 weeks for CDDP alone). No significant differences in toxicity were detected between the two arms; myelosuppression, alopecia, and peripheral neuropathy occurred more frequently with CDDP plus VDS and there was one lethal episode of hepatorenal syndrome in the CDDP plus VDS arm. Among the variables Eastern Cooperative Oncology Group (ECOG) performance status (PS), age, sex, stage, weight loss, serum lactate dehydrogenase (LDH) level, albumin level, histologic cell type, and chemotherapy arm, only chemotherapy arm was a significant factor leading to a major response (P = 0.019, multiple logistic regression analysis). The significant predictors of survival were PS (P = 0.000), sex (P = 0.000), and stage (P = 0.002) (Cox's proportional hazards model), with a PS of 0 or 1, female sex, and lower stage yielding the best survival. Although a significantly higher response rate was obtained in the combination arm than in the single agent arm, the survival benefit to patients receiving such combination chemotherapy was not determined and more effective chemotherapy regimens are required.
Intravenous infusions of nicardipine in a dose insufficient to lower blood pressure prevented the generation of the basilar artery spasm provoked by oxyhemoglobin (oxyHb) injected intracisternally in anesthetized dogs. The plasma concentration of nicardipine was comparable to that sufficient to suppress the oxyHb-induced contraction in isolated dog basilar arteries. Nicardipine appears to be similarly effective in antagonizing the vasoconstrictor action of oxyHb in vivo and in vitro.
In order to evaluate the preventive efficacy, safety and usefulness of mesna (Sodium 2-mercaptoethane sulfonate) against ifosfamide-induced urinary disorders, a placebo-controlled double-blind comparative study was performed. Ifosfamide was administered by intravenous drip infusion at a daily dose of 2 g/m2 for 5 consecutive days, and mesna was intravenously administered at 20% of the ifosfamide dose, three times daily for 5 consecutive days. The results obtained are as follows. (a) Of 101 accrued patients, 91 patients were evaluated consisting of 45 for the mesna group and 46 for the placebo group. There was no intergroup difference in the number of the evaluated cases and patient characteristics. (b) Micturition pain and feeling of residual urine graded as moderate or severe were not observed for the mesna group, but were observed for the placebo group with incidences of 19.6% (9/46) for micturition pain and 15.2% (7/46) for feeling of residual urine; the intergroup differences in the appearance of these urinary symptoms were statistically significant (P = 0.0003 for micturition pain; P = 0.0009 for feeling of residual urine). The incidence of hematuria graded as moderate or severe was 6.7% (3/45) in the mesna group, which was significantly lower than the 32.6% (15/46) in the placebo group (P = 0.0008). (c) No side-effect attributable to mesna was observed. (d) A judgment of "useful" was obtained in 80.0% (36/45) of the patients treated with mesna, which was significantly higher than the 34.8% (16/46) of the patients treated with placebo (P = near 0). On the basis of the above results, we conclude that the preventive efficacy, safety and usefulness of mesna against ifosfamide-induced urinary disorders have been well demonstrated in this study.
Oxyhemoglobin (Oxy-Hb) produced a concentration-dependent contraction of monkey, dog, and bovine cerebral artery strips. Treatment of Oxy-Hb with ascorbic acid suppressed the ability of Oxy-Hb to contract the arteries, especially in the monkey arteries. The ability of intracisternally applied Oxy-Hb to constrict the basilar artery in anesthetized dogs was diminished when Oxy-Hb was treated previously with ascorbic acid (AsA-Hb). The contraction caused by Oxy-Hb was suppressed by treatment with indomethacin and aspirin in isolated bovine cerebral arteries. Endothelium-dependent relaxations elicited by substance P and relaxations induced by stimulation of the vasodilator nerves with nicotine were suppressed by treatment with Oxy-Hb and AsA-Hb; however, the inhibitory effect of AsA-Hb was markedly less. Oxy-Hb attenuated nitroglycerin-induced relaxations in a dose-dependent fashion, whereas AsA-Hb in concentrations up to 1.6 x 10(-5) M did not significantly influence the relaxations. It is concluded that incubation of Oxy-Hb with ascorbic acid alters markedly the biological activity of Oxy-Hb; the vasoconstrictor activity is suppressed, and the ability to diminish vasodilator actions is minimized. These findings provide a rationale for the use of ascorbic acid in cisternal irrigation to prevent the development of cerebral vasospasm after a subarachnoid hemorrhage.
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Isolation of Rhodococcus equi from the submaxillary lymph nodes of pigs, with or without caseous lymphadenitis, and typing of the isolates by two serological methods were carried out. The rate of isolation of the organisms from the lymph nodes of pigs was 5 times higher in the lymph nodes with caseous lymphadenitis than in those without the lesion. Of 219 isolates, 146 (66.7%) were typable by the method of Prescott, while all the 219 isolates (100%) were typable by the method of Nakazawa et al. The most frequently isolated were serotype 2 of Prescott (identical to serogroup 16 of Nakazawa et al.), and serogroup 3 of Nakazawa et al., which did not correspond with any serotypes of Prescott. Serotypes/serogroups of R. equi from pigs were thus first clarified in Japan.
Surgery of a basilar bifurcation aneurysm is a very difficult operation in neurosurgery. For the treatment of this lesion, two methods are widely used at present: one is the subtemporal approach developed by Drake and the other is the pterional approach by Yasargil. With either approach, however, the treatment of a basilar bifurcation aneurysm accompanied by megadolichobasilar anomaly is difficult and hazardous due to the necessity for excessive retraction of the brain, nerves and vessels. Recently we successfully treated two cases of ruptured basilar bifurcation aneurysm complicated with megadolichobasilar anomaly by the trans-third ventricle approach. The floor of the third ventricle was already partly destroyed by aneurysmal rupture in both cases. It was required to make a small split in the third ventricle floor in order to get a wider operative field. Postoperatively, however, no influence from the splitting of the floor was seen. An experimental study was carried out in dogs to determine the influence from the destruction of the floor of the third ventricle. Using microsurgical techniques, the third ventricle floor was opened along the midline. Dogs were sacrificed 30 days after surgery. The following items were evaluated before, during, and after surgery: clinical symptom, blood pressure, pulse, body temperature, serum electrolytes, serum osmotic pressure, pituitary hormones (anterior lobe), cortisol, ADH (2.5mol NaCl loading test), electroencephalogram, cerebral blood flow and pathological change. No significant abnormalities could be detected in endocrine and metabolic functions, and no histological changes were seen around the hypothalamus. In conclusion, it is justified to split the third ventricle floor along the midline if it is indicated.
Though copper (Cu)-handling workers are known to be at risk to develop metal fume fever and acute respiratory failure, very little is known about the metabolic fate and pulmonary toxicity of Cu compounds deposited in the lung. We have investigated time-course and dose-related changes in Cu contents, the production of metallothionein (MT) and inflammatory responses in the rat lung following intratracheal instillation of cupric sulfate (CuSO4). Intratracheally instilled Cu was cleared rapidly from the lung with a half-time of 7.5 h. Copper-binding MT was induced in the lung tissue following Cu instillation and the amount of MT increased with the dose of CuSO4. However, the production of MT contributed little to the accumulation of Cu in the lung. The pulmonary toxicity of CuSO4 was evaluated by examining time-course and dose-effect profiles of cytological and biochemical inflammatory indices (enzymes, protein and elements) retrieved in bronchoalveolar lavage fluids. These results revealed that the inflammatory indices reached maximum values in their activities and contents at 12 h to 3 days after instillation and a dose of 5 micrograms Cu/rat was sufficient to produce acute inflammatory responses in the rat lung.
Metabolic behavior and pulmonary toxicity of yttrium chloride (YCl3) deposited in the lung was investigated. Yttrium chloride was instilled intratracheally into rats and the time-course and dose-related changes in distribution of Y between lung tissue and bronchoalveolar lavage fluid (BALF) and pulmonary inflammatory responses were investigated. Pulmonary clearance of Y was very slow and the half-life was estimated to be 168 days. Yttrium content in the supernatant of BALF did not exceed 5 micrograms Y/lung even when a dose of 200 micrograms Y/rat was administered, suggesting that the alveolar surface fluid could retain at most 5 micrograms Y. On the other hand, Y content in the pellet of BALF changed with the number of macrophages retrieved in BALF in both time-course and dose-response experiments. Transmission electron microscopy and X-ray microanalysis suggested that Y was localized in lysosomes of alveolar and interstitial macrophages, and basement membranes. These results clearly explain the long pulmonary half-life of Y. beta-Glucuronidase activity and calcium and phosphorous contents in the supernatant of BALF increased significantly even at the lowest dose (10 micrograms Y/rat). Comparative dose-effect profiles of lactate dehydrogenase activity in BALF supernatant revealed that 1 mol of YCl3 is equivalent to about one-third mole of cadmium compounds and about 3 mol of zinc oxide in the potency for acute pulmonary toxicity.
Urethritis in males and cervicitis in females, which were sexually transmitted diseases, were treated with NY-198, a new quinolone antibiotic, and its efficacy was studied. Seventeen male patients with gonorrheal urethritis were administered a single 300 mg dose of NY-198. The efficacy rate on the 3rd day after administration was 100%, but it was 85.7% on the 7th day due to recurrence in 1 patient. The results of treatment of non-gonorrheal infections were as follow. In this treatment, NY-198 was administered in a daily dose of 600 mg in 3 divided doses for 14 consecutive days. In the treatment of chlamydial urethritis of males, the efficacy rate in 26 patients was 84.6% on the 7th day and 84.0% on the 14th day in 25 patients. In the treatment of chlamydial cervicitis, the efficacy rate was 100% on both the 7th (3/3) and 14th (6/6) days. In the treatment of non-gonorrheal and non-chlamydial cervicitis, the efficacy rate was 100% on the 7th day (1/1) and 50% (1/2) on 14th day. The efficacy rate in all 40 males with non-gonorrheal urethritis was 85.0% on the 7th day and 88.9% for 36 patients on the 14th day, while that in all 4 females with cervicitis was 100% on the 7th day and 87.5% on the 14th day. No side effects were seen in any of the patients. Overall, NY-198 had an efficacy rate of 80% in the treatment of chlamydial infections. NY-198 was found to be a useful drug which is efficacious in the treatment of all STD-related microbes such as gonococci and chlamydia.
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Thirty-nine previously untreated small cell lung cancer patients received cyclophosphamide (CTX) + adriamycin (ADM) + vincristine (VCR) (CAV). The doses initially used were CTX 1,000 mg/body day 1, ADM 50 mg/body day, VCR 1 mg/body day, 8, 15 or 2 mg/body day(group A). Later, CTX 1,000 mg/m2 day, ADM 60 mg/m2 day, VCR 1.4 mg/m2 day were used. All patients had PS 0-3, 24 had limited disease (LD) and 15, extensive disease (ED). The overall response rate and the complete response (CR) rates were 63% (15/24) and 21% (5/24) for LD, and 21% (3/14) and 0% (0/14) for ED, respectively. The median response durations were 22 weeks for LD and 33 weeks for ED. The median CR duration in LD patients was 23 weeks. Twelve LD and 1 ED patient received thoracic radiotherapy (RT) optionally after 2-4 courses of CAV therapy. Eventually, 8 patients achieved CR. The median survival for LD, ED and all cases were 43 weeks, 37 weeks and 41 weeks, respectively. The 1, 2 and 3-year survival rates were 42, 25 and 21% for LD, and 40, 7 and 0% for ED. Three patients were long-term disease-free survivors (greater than 3 years), and these had LD and received RT. There were 3 chemotherapy-related deaths (2 patients with leukopenia + infection, 1 patient with drug-induced pneumonitis). The survival results of CAV therapy in our hospital were comparable with the recent results of chemotherapies available against small cell lung cancer.
Phase II studies of single agent and CDDP-based two drug combination were performed in 189 patients with inoperable non-small cell lung cancer. Six drug regimens were performed: CDDP alone, VDS alone, Epi-ADM alone, CDDP + VDS, CDDP + CPA, CDDP + ADM. The response rates were 15.4% (6/39) with CDDP alone, 8.0% (2/25) with VDS alone, 6.1% (2/33) with Epi-ADM alone, 26.7% (8/30) with CDDP + VDS, 14.3% (4/28) with CDDP + CPA, 17.6% (6/34) with CDDP + ADM and one CR was performed with CDDP + ADM. In patients with no prior chemotherapy, the response rates were 20.0% (6/30), 11.8% (2/17), 12.5% (2/16), 26.7% (8/30), 16.0% (4/25) and 25.0% (3/12), respectively. The median survival times were 25, 27, 23, 33, 25, and 45 weeks, respectively. The efficacy of CDDP in non-small cell lung cancer patients was re-confirmed, and that of CDDP + VDS, CDDP + ADM was suggested. No death due to toxicity occurred and toxicity was generally tolerable.
The aim of combined modality treatment of lung cancer is to improve control of both local and metastatic disease. Retrospective reviews of the combined RT and CT modality in limited-stage small cell lung cancer (SCLC) showed an improvement of median survival and long term survival compared with CT alone. Among reports of 7 prospective trials in which patients were randomized so as to receive CT alone or CT with chest irradiation, combined modality treatment significantly increased the CR rate in 3/3, and the overall survival was significantly prolonged in 3/7. Concurrently combined modality treatment has a modest survival benefit in limited stage SCLC. Our phase 2 study combining RT with cisplatin-containing CT showed better improvement of response and survival than CT alone in non-small cell lung cancer (NSCLC). Four reports of prospective randomized studies have been performed to determine whether combined RT and combination chemotherapy might be better than RT alone in limited-stage NSCLC. Two of these studies demonstrated a survival and response advantage for the combined modality treatment. However, this approach for NSCLC reported so far has been disappointing, because of relative lack of effectiveness of the present CT.
Twenty-seven patients with advanced and previously untreated non-small cell carcinoma of the lung received combination chemotherapy with CDDP (100 mg/m2 iv on day 1) and etoposide (100 mg/m2 iv on day 2, 4 and 6). Eleven partial responses were observed (response rate of 40.7%), and the median survival of patients was 44.4 weeks. Toxicity was tolerable with moderate myelosuppression. This combination chemotherapy should be recommended for further clinical trials.