Phase I and pharmacologic study of oral (E)-2′-deoxy-2′-(fluoromethylene) cytidine: on a daily × 5-day schedule

(E)-2-deoxy-2-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3–4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.     

Local Control and Cosmetic Outcome after Sector Resection with or without Radiation Therapy for Early Breast Cancer

Breast conserving surgery and radiation therapy (RT) can achieve a more favorable cosmetic outcome than mastectomy in patients with early breast cancer. However, it is widely recognized that RT is an impediment to improving the cosmetic outcome. Between 1985 and 1993, 113 patients were enrolled in a prospective randomized study to examine whether or not RT could be avoided following sector resection in patients with Stage I and II (UICC) invasive breast cancer. There was no significant difference in the 8 year local recurrence free survival rate between the RT and non-RT groups (92.3% versus 89.8% respectively). The characteristics of suitable patients would be negative nodes and microscopically negative resection margins. In conclusion, sector resection without RT is a reasonable option for some patients with early breast cancer.     

The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer: a comparative study with X-ray computed tomography

We evaluated the usefulness of fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) in the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer and then compared the findings with the results of X-ray CT by region based on the histological diagnoses. We examined 29 patients with non-small cell lung cancer. One hundred and thirty-two mediastinal lymph nodes were surgically removed and the histological diagnoses were confirmed. FDG PET images, including 146 mediastinal regions, were visually analysed and the mediastinal lymph nodes were scored as positive when the FDG uptake was higher than that in the other mediastinal structures. On the X-ray CT scans, any mediastinal lymph nodes with a diameter of 10 mm or larger were scored as positive. All three examinations were successfully performed on 71 regions. For FDG PET, we found a sensitivity of 76%, a specificity of 98% and an accuracy of 93%. On the other hand, for X-ray CT a sensitivity of 65%, a specificity of 87% and an accuracy of 82% were observed. A significant difference was observed in respect of both specificity and accuracy (P<0.05). Based on the above findings, FDG PET is suggested to be superior to X-ray CT when used for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer.     

Protective action of diethyldithiocarbamate and carbon disulfide against acute toxicities induced by 1,1-dichloroethylene in mice

In male mice of ddY strain, a single dose of 1,1-dichloroethylene (1,1-DCE, 0.1 ml/kg, ip) produced severe renal damage at 24 hr, as evidenced by elevations in plasma urea nitrogen concentration and kidney calcium content and by massive renal tubular necrosis, while hepatic damage was less severe. A precipitous decrease in body temperature started as early as 30 min after administration of 1,1-DCE and lasted for 24 hr. Glutathione concentrations decreased in the liver and kidney, with a rebound increase seen in the former but not in the latter tissue. In carbon tetrachloride-poisoned mice, the renal toxicity of 1,1-DCE was markedly potentiated. Pretreatment with either diethyldithiocarbamate (DTC) or carbon disulfide (CS₂) blocked all of these 1,1-DCE-induced toxic manifestations in normal and carbon tetrachloride-poisoned mice. Both agents, however, did not prevent the hypothermia induced by monochloroacetic acid or chloroacetyl chloride, proposed active metabolites of 1,1-DCE. Since DTC and CS₂ inhibited hepatic and renal microsomal drug metabolizing enzyme activities (Masuda and Nakayama, 1982, Masuda and Nakayama, 1983), it is probable that the protective action of DTC and CS₂ against renal and hepatic injury induced by 1,1-DCE may be due to an inhibition of the metabolic activation of 1,1-DCE to its proposed epoxide in each organ. The action of DTC given po may be mediated by CS₂ produced in the stomach. The hypothermia induced by 1,1-DCE may not result from a direct action of 1,1-DCE per se, but by its metabolites.     

Comparative study on the cardio-respiratory change during prostaglandin E1-induced hypotension in the patients in the supine and prone position

Prostaglandin E₁-induced hypotension (25% reduction from the preadministration level in mean arterial pressure) was applied to thirteen patients. Eight patients among them were operated in the supine position (group I) and other five in the prone position (group II). The maintenance dose of PGE₁ was considerably lower in group II than in group I (0.067µg·kg^–1·min^–1 vs. 0.119µg·kg^–1·min^–1). In group I, there was a significant increase in CI, with a significant decrease in SVRI and PVRI during PGE₁-induced hypotension. Such a high dose of PGE₁ (0.119µg·kg^–1·min^–1) was considered to have a direct dilating action on the systemic resistance bed as well as on the pulmonary vasculature. It was considered that the suppression of hypoxic pulmonary vasoconstriction could be a mechanism to increase venous admixture during PGE₁-induced hypotension. In group II, there was no significant increase in CI, and no significant decrease in SVRI and PVRI. PGE₁-induced hypotension can be safely applied to the anesthetized patients, but we should be careful to apply it to the patients in the prone position, because lower dose of PGE₁ can induce severe hypotension, which is not accompanied by the increase in CI as occures in the patients in the supine position.(Hirose M, Yoda K, Sakai K, et al.: Comparative Study on the cardio-respiratory change during prostaglandin E₁-induced hypotention in the patients in the supine and prone position. J Anesth 5: 30–35, 1991)     

Serum-free coculture of stromal and epithelial cells from benign prostatic hyperplasia with keratinocyte growth factor

We developed a serum-free coculture model of benign prostatic hyperplasia (BPH) to clarify whether stromal cells stimulate growth of epithelial cells from BPH tissues. Epithelial and stromal cells from freshly isolated BPH tissue were cultured separately in defined serum-free WAJC 404/RPMI 1640 medium supplemented with insulin, transferrin, selenium, hydrocortisone, bovine serum albumin, epidermal growth factor, basic fibroblast growth factor and keratinocyte growth factor. (3)H-Tdr incorporation into epithelial cells and stromal cells was used as a measure of proliferation. When epithelial cells were cocultured with stromal cells, (3)H-Tdr incorporation into epithelial cells was increased in comparison to that in epithelial cells cultured alone. Dihydrotestosterone significantly increased this effect. It is likely that the in vitro coculture model reported here will be useful for isolating and understanding stromal cell-derived paracrine growth factor(s).     

Reduction in formation of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP)-induced aberrant crypt foci in the rat colon by docosahexaenoic acid (DHA)

Docosahexaenoic acid (DHA), a major component of fish oil, suppresses the formation and growth of aberrant crypt foci induced by 1,2- dimethylhydrazine and azoxymethane. In the present study we examined the effects of intragastric gavage administration of DHA on the yield of rat colonic aberrant crypt foci due to treatment with a heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which induces colon cancer in male F344 rats and is considered to be a possible human colon carcinogen. Male F344 rats were given a standard diet (AIN-76A) and received 10 doses of PhIP (75 mg/kg body wt, by intragastric intubation, on days 1-5 and 8-12) with or without intragastric application of 1 ml DHA 4 h prior to each carcinogen treatment, followed by further DHA dosing. The numbers of PhIP-induced aberrant crypt foci per colon after 4 and 12 weeks DHA administration were significantly reduced to 47 and 38% respectively of the values obtained when PhIP alone was used. The mean number of aberrant crypts per focus was also decreased by DHA treatment. At week 4 the PhIP-DNA adduct levels in the colon of rats from the PhIP+DHA group were approximately two thirds of the PhIP group value. The results thus suggest that DHA exerts a preventive effect on PhIP-induced colon carcinogenesis.      

Relapsed non-Hodgkin's lymphoma: detection and treatment

PURPOSE: To evaluate the optimal management strategy during clinical remission and after relapse in patients with non-Hodgkin's lymphoma (NHL). METHODS: Sixty-six patients with relapse of NHL from a state of clinical remission between 1987 and 1997 were analyzed retrospectively. The pattern of relapses, diagnostic methods used for relapses, and clinical outcome of salvage treatment were analyzed with attention to time after the achievement of clinical remission. RESULTS: Thirty-three relapses (50%) occurred within 12 months, and the remainder occurred gradually from 12-48 months after the first remission. Diagnosis of relapse in 61 of the 66 patients (93%) was made at unscheduled evaluations prompted by symptoms, on physical examinations, or because of high LDH levels. The 1- and 5-year cause-specific survival rates after relapse were 56.7% and 39.4%, respectively. The 1- and 5-year relapse-free survival rates were 50.1% and 35.0%, respectively. The 5-year relapse-free survival rate in patients with late relapse (49.5%) was significantly better than in those with early relapse (21.2%) (p<0.01). CONCLUSION: Time to relapse may be a useful factor to determine optimal management strategy in NHL patients.     

The influence of human T lymphotropic virus type I infection on the outcome of cardiovascular surgery

OBJECTIVE: Human T lymphotropic virus type I infects CD4(+) T cells and affects cell-mediated immunity. Cardiopulmonary bypass transiently alters lymphocyte subsets, resulting in a reduction in CD4(+) T cells and an increase in CD8(+) T cells. We proposed that cardiovascular operations and human T lymphotropic virus type I infection may act synergistically, resulting in serious damage to cell-mediated immunity. METHODS: A total of 517 consecutive patients who were preoperatively screened for anti-human T lymphotropic virus type I antibody and underwent cardiovascular operations with cardiopulmonary bypass were enrolled in this study. Of the 517 patients, 82 (16%) had positive test results for anti-human T lymphotropic virus type I antibody. The surgical outcome of patients with positive and negative results for anti-human T lymphotropic virus type I antibody was analyzed retrospectively. RESULTS: There was no difference between the 2 groups with respect to early mortality. Distribution of survival curve was also not significantly different (P =.5; mean follow-up duration, 2.4 +/- 1.8 years [range, 0-9.4 years] and 3.2 +/- 2.8 years [range, 0-9.8 years]) in the groups with positive and negative antibody results, respectively). In particular, long-term follow-up did not reveal adult T-cell leukemia or human T lymphotropic virus type I-associated myelopathy, and occurrence of neoplasm did not differ between groups. Early infectious complication was, however, significantly higher in the group with positive antibody results than in the group with negative results (P =.02). Logistic regression analysis revealed human T lymphotropic virus type I infection as a significant risk for this complication (P =.04; odds ratio, 2.5; 95% confidence interval, 1. 0-5.8). CONCLUSION: A combination of human T lymphotropic virus type I infection and cardiovascular operation is believed to increase the potential risk of infectious complications shortly after the operation. However, this synergistic effect seems to be transient and has little influence on long-term prognosis.