A case of basal cell carcinoma of the nipple and areola with intraductal spread.

We report an 82-year-old Japanese woman with basal cell carcinoma of the left nipple and areola extending into the lactiferous duct. The patient developed a small papular lesion of the left areola about 1 year before admission. The lesion, which had slowly progressed to involve the nipple, had become symptomatic showing weeping and bleeding. Mammography revealed microcalcification in the nipple. Although Paget's disease was suspected from these clinical features, histologically basal cell carcinoma was diagnosed. There was no axillary lymphadenopathy, and no evidence of distant metastasis. The lesion of the nipple and areola was resected with a 2 cm free margin along with the underlying mammary tissue. The patient has remained well without signs of recurrence for 2 years after surgery. We reviewed cases of basal cell carcinoma of the nipple or areola and discuss considerations and problems of this rare tumor.

[Absence of cross resistance between an irinotecan plus cisplatin combination and raltitrexed (ZD1694) in two patients with advanced colorectal cancer].

Two patients with advanced colorectal cancer were consecutively administered two different chemotherapeutic regimens. The first patient showed an initial response to combination treatment with irinotecan plus cisplatin, but then progressed. He subsequently responded to treatment with a novel thymidylate synthase (TS) inhibitor, raltitrexed. The second patient, who progressed after exhibiting a response to raltitrexed, subsequently responded to irinotecan/cisplatin combination therapy. In conclusion, no clinical cross resistance between the regimens of irinotecan/cisplatin combination therapy and raltitrexed was observed in these patients with advanced colorectal cancer.

Characterisation of a synergistic interaction between a thymidylate synthase inhibitor, ZD1694, and a novel lipophilic topoisomerase I inhibitor karenitecin, BNP1100: mechanisms and clinical implications.

We developed a combination protocol for inhibitors of thymidylate synthase (TS) and DNA topoisomerase I (Topo I) that can exert highly lethal effects in vitro against HCT-8 human colorectal cancer cells. The specific schedule was constructed so that a TS inhibitor could induce not only primary DNA damage but also cellular conditions optimal for the efficient action of a Topo I inhibitor. The initial drug treatment consisted of a brief exposure to a quinazoline-based antifolate, ZD1694. After an interval of approximately one cell-doubling time, cells were exposed for 8-24 h to BNP1100, a Karenitecin-class 7-thiomethyl-camptothecin, in the presence of 1-10 microM thymidine; the latter acted as a crucial factor to promote the collision of moving replication forks with the drug-stabilised DNA-Topo I cleavable complexes even under continuous TS inhibition. Clonogenic analyses confirmed that these mechanistically distinct drugs at clinically achievable concentrations worked in a highly synergistic manner, with a maximum effect abolishing the viability of virtually all cancer cells (> 99.9%). The pretreatment with ZD1694 increased the amount of DNA-bound Topo I by up to 4-fold and the DNA-damaging capability of BNP1100 by up to 15-fold. The possibility of at least four DNA-damaging pathways is proposed which might have resulted from the individual actions of TS and Topo I inhibitors as well as their concerted actions. Taken together, the present findings provided a logically permissible explanation as to why TS and Topo I inhibitors in concerted interactions induced a highly lethal effect which was more than a simple additive effect. Since these drugs are effective specifically on actively proliferating cancer cells, but not on non-cycling G0/G1 cells, this mechanism-based protocol may warrant consideration for clinical verification.

Metallothionein modulates the carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine in mice.

We examined the carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in transgenic mice deficient in the metallothionein (MT) I and II genes and in control (129/Sv) mice. Both strains of mice were given BBN for 8 weeks with or without Zn treatment. All mice were killed at 12 weeks after the cessation of BBN administration. BBN induced bladder tumors in 75% of MT null mice and in 43% of 129/Sv mice. The average number of bladder tumors per mouse was significantly higher in MT null mice (1. 18 +/- 0.27) than in 129/Sv mice (0.43 +/- 0.20). Zn treatment suppressed the carcinogenicity of BBN in 129/Sv mice but not in MT null mice. Histopathological examination of the tumors revealed that the malignant potential of bladder tumors in 129/Sv mice was greater than that in MT null mice. These results indicate that MT is an important modulator of carcinogenicity of BBN in the bladder of mice.

[Advances in endoscopic therapies for cancers of the digestive tract].

Endoscopic therapies for the treatment of cancers of the digestive tract have been improved. Today, some early cancers can be curatively treated by endoscopy (endoscopic polypectomy, endoscopic mucosal resection, heatprobe method, etc.). In addition, endoscopic local injection chemotherapy is performed for some advanced cancers as an adjuvant therapy. Recent progress in endoscopic therapies for cancer is reviewed in this paper, including their historical background. Improvements in these endoscopic treatment methods are expected to provide increased advantages for the treatment of patients with cancer in the near future.

[Prophylactic effect of black tea extract as gargle against influenza].

We examined whether gargling with black tea prevents influenza infection. Tests were carried out during a five month period (October 1992 to March 1993). The control group that followed their normal daily routine, whereas the test group that gargled with 0.5 w/v% black tea extract twice daily (at 8 a.m. and 5 p.m.). Influenza viruses were isolated from influenza patients and an antigen analysis was carried out. As a result, two strains of influenza A viruses (H3N2) and ten strains of B virus were detected. An HI test was done using paired sera of the control group and the test group. The HI titers raised a four fold or greater in 48.8% (61/125) in the control group and 35.1% (35/134) in the test group. There was a significant difference (p < 0.05) between the control and test groups. These results indicate that black tea extract is effective as a prophylactic agent against influenza infection.

Effects of the new cognition-enhancing agent nefiracetam in rats with cerebral embolism.

The effects of nefiracetam (DM-9384, CAS 77191-36-7) on the learning behavior and cholinergic and GABAergic neuronal transmitter systems of rats with experimentally-induced cerebral embolism were investigated. Cerebral embolisms were induced in male Wistar rats by injection of 800 microspheres 50 microns in diameter via the left internal carotid artery under 2% halothane anesthesia. Daily oral administration of nefiracetam (30 mg/kg/d) was started 9 days after embolization. Nefiracetam caused significant (p < 0.05) improvement of deficits in the learning of both water maze and passive avoidance tasks beginning 22 days after embolization of the rats. The drug also significantly restored decreases in cortical choline acetyltransferase (p < 0.05) and hippocampal glutamic acid decarboxylase activities (p < 0.01) in the embolized cerebral hemisphere and significantly increased cortical choline acetyltransferase (p < 0.05) and acetylcholinesterase activities (p < 0.05) in the contralateral cerebral hemisphere 21 days after embolization. These results demonstrate that nefiracetam improves cognitive dysfunction in the late phase in embolized rats and suggest that the effect is at least partly due to the increase in glutamic acid decarboxylase, choline acetyltranseferase and acetylcholinesterase activities.

[The clinical significance of PIVKA-II determination in patients with hepatocellular carcinoma: a comparative study with alpha-fetoprotein].

The changes in the plasma level of PIVKA-II (Protein Induced by Vitamin K Absence or Antagonist-II) following the treatment or progress of the disease was studied in 60 patients with hepatocellular carcinoma. The positivity rate determined by the changes in PIVKA-II was 58.4 percent (35/60 cases) and was about the same as those reported so far, all of which were obtained by a single determination of PIVKA-II. Plasma PIVKA-II was elevated in 61.9 percent (13/21 cases) of alpha-fetoprotein negative patients and it was almost identical with the overall positivity rate. In parallel with serum alpha-fetoprotein, the plasma level of PIVKA-II was decreased after the surgery or transcatheter arterial embolization and was increased when the recurrence or progress of the disease was observed. Furthermore, the nonspecific elevation of PIVKA-II due to the associated liver cirrhosis or chronic hepatitis was infrequent compared with that of alpha-fetoprotein. In 18 cases positive with both PIVKA-II and alpha-fetoprotein, a close correlation (R = 0.91) was observed between the changes of these markers during the progress or treatment of the disease. Thus, it was suggested that determination of PIVKA-II in blood might be useful not only in the diagnosis but in monitoring the progress or the effectiveness of treatments in hepatocellular carcinoma.

[Effects of cysteine compounds on antibiotics I. Effects of L-cysteine and its derivatives on the potency of antibiotics (author's transl)].

Various derivatives of L-cysteine obtained by conversion to an -S-S- bond in the mucoprotein by means of -SH in the chemical structure are widely used as expectorants because they show mucous dissolving action. Recently, there have been reports that L-cysteine derivatives lower the potencies of various antibiotics. Various types of antibiotics and cysteine-type expectorants are often used concomitantly for the treatment of bacterial infections in respiratory tract diseases, and any decrease in the antibiotic potency presents a major therapeutic problem. We investigated the effects of four cysteine derivatives on 12 antibiotics, ampicillin (ABPC), amoxicillin (AMPC), sulbenicillin (SBPC), cefazolin (CEZ), cephalexin (CEX), cephalothin (CET), oxytetracycline (OTC), doxycycline (DOTC), minocycline (MINO), erythromycin (EM), ribostamycin (VSM) and lincomycin (LCM), widely used clinically in vitro with the minimum inhibitory concentration (MIc) obtained by the liquid dilution method as an index. L-Cysteine, acetylcysteine, ethylcysteine and mecysteine lowered the potencies of almost all of the antibiotics at high concentrations (500 mcg/ml), but at low concentrations (12.5 mcg/ml), mecysteine lowered the potencies of only three antibiotics and L-cysteine those of only four antibiotics, while acetylcysteine decreased the potencies of six and ethylcysteine those of seven antibiotics.

The inhibitory effect of acute administration of excess iodide on the formation of adenosine 3', 5'-monophosphate induced by thyrotropin in mouse thyroid lobes.

In a previous paper, we demonstrated that an inhibitory action of excess iodide on thyrotropin-induced thyroid hormone secretion occurs at a site subsequent to the generation of cyclic AMP. In the present study, however, we have found that thyroidal cyclic AMP formation induced by thyrotropin in vitro was markedly inhibited by the acute administration of excess iodide to mice fed a low iodine diet. In contrast, excess iodide failed to produce inhibition in animals fed a regular diet. In vitro stimulation by long-acting thyroid stimulator (LATS), prostaglandin E2, and 4-methylhistamine of cyclic AMP formation in mouse thyroid lobes was also significantly inhibited by the acute in vivo administration of excess iodide. The inhibition was completely relieved by the administration of methimazole prior to excess iodide. Furthermore, it has been shown that thyroid adenylate cyclase activity induced by thyrotropin was markedly depressed by excess iodide under similar experimental conditions. Therefore, it is suggested that one of the inhibitory actions of excess iodide is on the adenylate cyclase-cyclic AMP system and further, that iodide can elicit its inhibitory action after its conversion to some form of organic iodine.

[Studies on the thyrotropin receptor in the thyroid: positive cooperativity of Concanavalin A binding and its biphasic effects on thyroid activation induced by thyrotropin (author's transl)].

Concanavalin A (Con A) was tested for its ability to affect thyroid activation induced by the thyroid stimulators in mouse thyroid tissues. Con A was found to have the biphasic stimulatory and inhibitory effects of thyrotropin (TSH)-induced cyclic AMP formation and endocytosis, a step in thyroid hormone secretion, in mouse thyroid tissues. Low concentrations of Con A potentiated TSH-stimulated cyclic AMP formation and endocytosis. In contrast, high concentrations of Con A markedly inhibited TSH stimulations. These effects were reversed by the addition of methyl-alpha-D-glucoside to the second preincubation medium (without Con A) prior to TSH. A high concentration of Con A alone did not depress the basal levels of cyclic AMP or basal glucose oxidation in thyroid tissues. A high concentration of Con A also inhibited cyclic AMP formation induced by prostaglandin E2 and the long-acting thyroid stimulator (LATS). Binding of 125I-labeled Con A to thyroid tissues increased with time up to 75 min and was very slowly reversible after attainment of equilibrium. Binding was directly proportional to tissue weight. Scatchard plot analysis on the binding of 125I-labeled Con A to thyroid tissues indicated a positive cooperativity which seemed to be well correlated to the biphasic effects.