Background. A number of studies have indicated that the ki‐67 proliferation index is of important prognostic significance for a variety of neoplasias. It was the aim of this study to investigate whether any correlation exits between the MIB‐1 proliferation index and various clinicopathologic parameters in squamous cell carcinomas of the esophagus from 72 patients (20 women: median age, 64 years; range, 45–79 years; and 52 men: median age, 61 years; range, 43–77 years). Methods. Proliferative activity was determined using an immunohistochemical method with monoclonal antibody MIB‐1 (ABC method), for tumor samples obtained from individuals who underwent esophagectomy in the period from 1983 to 1991. The percentage proliferation index (PI) was calculated as the number of positive cells divided by the total number of cells examined. Thirty‐nine patients (54%) died of recurrence of esophageal cancer, with a median survival span of 15 months (range, 1–58 months). Thirty‐three patients (46%) were still alive at the time of this study; their median follow up was 57 months (range, 40–98 months). Results. Significant differences between proliferative index values were recorded for the following parameters: survival rate, P < 0.0001; presence of lymph node metastasis, P < 0.05; size of the primary esophageal lesion, P < 0.01; proliferation pattern of the tumor, P < 0.01; and age of the patients, P < 0.05. No correlation was found regarding histologic differentiation, clinical stage, location of the lesion, intraepithelial cancerous spread, lymphatic and blood vessel invasion, and sex of the patients. Conclusion. The MIB‐1 proliferation index may be a powerful prognostic marker for patients with squamous cell carcinomas of the esophagus. Cancer 1995;76:358–66.

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The pharmacological activity of DSP-6952, a novel compound was investigated, compared to that of clinically efficacious gastrointestinal (GI) prokinetic 5-hydroxytryptamine (5-HT) receptor agonists. DSP-6952 had a strong affinity of Ki = 51.9 nM for 5-HT receptor, and produced contraction in the isolated guinea pig colon with EC of 271.6 nM and low intrinsic activity of 57%, similar to tegaserod and mosapride. In the development of the 5-HT receptor agonists, cardiovascular risk was deliberately evaluated, because some related prokinetics were reported to cause with cardiovascular adverse events, such as ventricular arrhythmias or ischemia. DSP-6952 showed minimal effects up to 100 μM in human ether-a-go-go-related gene (hERG) channels or guinea pig cardiomyocytes. In telemetered conscious monkeys, DSP-6952 did not affect blood pressure or any electrocardiogram (ECG) up to 180 mg/kg, p.o.; however, DSP-6952 transiently increased heart rate, as well as in anesthetized dogs. The positive chronotropic effects of DSP-6952 were completely antagonized by a 5-HT receptor antagonist, and another 5-HT receptor agonist, TD-5108 also increased heart rate. These effects are considered a class effect seen in clinically developing and marketed 5-HT receptor agonists, and have not been regarded as a critical issue in clinical use. DSP-6952 did not induce contraction in the rabbit coronary artery up to 100 μM, which differed from tegaserod or sumatriptan. These results show that DSP-6952 does not have cardiac ischemic risk via coronary vasoconstriction. In conclusion, DSP-6952 is a promising GI prokinetic compound with partial 5-HT receptor agonistic activity as well as a favorable cardiovascular safety profile.

A series of 8 rat and 16 mouse invasive bladder carcinomas were investigated for the presence of silver-stained nucleolar organizer regions (AgNORs) to clarify whether this parameter is applicable to the estimation of their invasive character. With regard to number of AgNORs per cell, neither rat nor mouse carcinomas showed any difference between invasive and noninvasive sites within the same tumor. However, the frequency of cancer cells bearing bizarre dots, irregular in size and shape, was significantly higher at sites of actual invasion. Quantitative data generated using an image analyzer revealed significantly lower values for NOR roundness and significantly larger NOR size in invasive sites than in noninvasive sites in all groups. Double staining for the proliferation marker proliferating cell nuclear antigen (PCNA) and AgNORs was performed on eight rat carcinomas and a close correlation between the two was confirmed. Thus the number of AgNORs in PCNA-positive cells was significantly greater than in PCNA-negative cells. Furthermore, a particularly strong correlation was observed for incidences of PCNA-positive cells and bizarre dots (P < 0.01). The quantitative data also demonstrated significant differences in size and shape of dots. It is concluded that AgNORs have diagnostic value for the invasive character of bladder carcinomas.

Abstract. In this study, the effects of atropine sulfate (atropine) on swallowing and cough reflex were evaluated in the two experimental models in conscious dogs. To evaluate the effects of atropine on swallowing, 1 mL of marker (contrast medium) was injected into the pharynx under X-ray exposure to induce swallowing. Baclofen, used as a positive control, caused marker congestion in the upper esophagus. In our experimental model, atropine (0.02 and 0.1 mg / kg, i.v.) dose-dependently increased not only the number of marker congestions but also that of the swallows. In addition, atropine significantly shortened the onset of first swallowing. In the evaluation of atropine effects on electrically evoked cough reflex induced by two electrodes implanted into the trachea, atropine strongly inhibited the number of coughs at 0.01 or 0.05 mg / kg accompanied with 0.01 or 0.05 mg / kg per hour (i.v.), respectively. These findings indicate that atropine has the potential of causing aspiration pneumonia through induction of swallowing disorder and inhibition of the cough reflex.