In vivo activity on murine tumors of a novel antitumor compound,N-β-dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]phenazine-6-carboxamide sodium salt (NC-190)

Summary A novel antitumor compound, N--dimethylaminoethyl 9-carboxy-5-hydroxy-10-methoxybenzo[a]-phenazine-6-carboxamide sodium salt (NC-190) was evaluated for its antitumor activity in experimental murine tumor systems. In the initial studies with P388 leukemia (i.p.-i.p.), NC-190 led to an increase of >200% in life span (ILS), and 75% of the mice were alive on day 30, when the optimal dose (50 mg/kg, days 1–5) was given. Additionally, the compound had significant activities against i.p. inoculated mouse L1210 leukemia, B16 melanoma, M5076 reticulum cell sarcoma, sarcoma 180, mouse hepatoma MH134, and rat Yoshida sarcoma and Yoshida ascites hepatoma AH130. The optimal dose resulted in a >280% ILS with a 30-day survival of 50% in mice with L1210 leukemia (100 mg/kg, days 1–5), a 156% ILS in mice with B16 melanoma (50 mg/kg, days 1–5), a 98% ILS with a 90-day survival of 25% in mice with M5076 reticulum cell sarcoma (25 mg/kg, days 1, 5, 9, and 13), a >300% ILS with a 60-day survival of 50% in mice with sarcoma 180 (50 mg/kg, days 3–10), a 148% ILS with a 60-day survival of 25% in mice with MH134 (25 mg/kg, days 1–5), a 129% ILS with a 60-day survival of 12.5% in rats with Yoshida sarcoma (12.5 mg/kg, day 3–10), and a >161% ILS with a 60-day survival of 50% in rats with AH130 (6.3 mg/kg, days 3–10). In the experiments with s.c. inoculated tumors, NC-190 not only inhibited tumor growth, but also increased the life span of mice with Lewis lung carcinoma or B16 melanoma. The 60-day survivors accounted for 60% and 30% in mice with Lewis lung carcinoma and B16 melanoma, respectively. The compound significantly inhibited the spontaneous lung metastasis of Lewis lung carcinoma by more than 90% when eight daily i.v. injections were given. NC-190 was active by the i.p., s.c., and i.v. routes. Five consecutive daily i.p. doses (days 1–5) were more effective than a single dose (day 1), two doses (days 1 and 5), or three doses (days 1, 5, and 9). NC-190 warrants further study as a potential antineoplastic agent against human neoplasms, as it has a broad spectrum of antitumor activity and inhibits metastasis.Abbreviations ILS increase in life span - MST median survival time - MMC mitomycin C - ADM adriamycin - CPA cyclophosphamide - 5-FU 5-fluorouracil     

Pulmonary fibrosis and lung carcinoma: a comparative study of metaplastic epithelia in honeycombed areas of usual interstitial pneumonia with or without lung carcinoma

Usual interstitial pneumonia (UIP), or idiopathic pulmonary fibrosis, has been considered to be associated with a high risk for lung carcinoma. To investigate this well-known but still equivocal relationship, we reviewed the clinical features of UIP autopsy cases with or without lung carcinoma (n = 32 and 38, respectively), and compared the morphology and cell kinetics of metaplastic epithelia in the honeycombed areas (n = 11, each group). Thirty-two of 70 UIP autopsy cases showed lung carcinomas. Clinically, UIP with lung carcinoma showed a male predominance (P = 0.001), a higher rate of smoking history (P = 0.001) and a later onset of UIP (P = 0.02), compared with UIP without lung carcinoma. Most of the carcinomas were peripheral in origin (90%), and 65% were topographically associated with honeycombed areas or the border between honeycombing and non-fibrotic areas. Quantitative assessment of the metaplastic epithelia in the honeycombed areas revealed that squamous metaplasia, but not cuboidal cell metaplasia or bronchial cell metaplasia, occurred more frequently in UIP with lung carcinoma than in UIP without lung carcinoma (P = 0.02). There were no significant differences between the two groups with regard to the labeling indexes of Ki-67 and p53 in the metaplastic epithelia, including squamous metaplasia. The degree of atypical squamous metaplasia was not different between the two groups. The quantitative predominance of squamous metaplasia in the honeycombed areas may not be a precursor for lung carcinoma, but might reflect a constitutional susceptibility of UIP patients to develop a lung carcinoma.     

Morphological changes in mouse sublingual gland parenchyma subjected to chorda tympani resection

Morphological changes in the mouse sublingual gland parenchyma subjected to parasympathetic nerve block were investigated. Mice were subjected to unilateral resection of the chorda tympani, near its point of joining with the lingual nerve. After 1, 2, 3, 5, 10 or 20 weeks, the mice were killed and their sublingual glands were removed and processed for light and electron microscopy. Two weeks after resection, the space between the adjoining lobules of the glands on the treated side began to be expanded, and by 10 weeks were 10 times the size of the spaces in the glands of the untreated mice. Three weeks after resection, the lobule area decreased to about 72% of the area of glands in the untreated mice and the acinus area to about 52%. However, no significant difference was seen between the numbers of acini in each group. Electron microscopy showed that the glands on the treated side contained fewer secretory granules than the glands in the untreated mice, though there was no difference in size. Neither the lobules of the glands on the treated side nor those of the glands of the untreated mice contained many TUNEL-positive cells. These findings suggest that following parasympathetic nerve resection, mouse sublingual gland acinar cells undergo atrophy with a reduction size rather than cell death.     

Relation between yawning behavior and central serotonergic neuronal system in rats

Summary Subcutaneously (s.c.) administered apomorphine (0.0125–0.4 mg/kg) or physostigmine (0.025–0.4 mg/kg) to rats elicited yawning. The dose-response curves were bellshaped. The peak effects of apomorphine and physostigmine were observed with a dose of 0.1 mg/kg of each drug. Yawning elicited by apomorphine (0.1 mg/kg) or physostigmine (0.1 mg/kg) was reduced by intraperitoneally (i.p.) administered 5-hydroxytryptophan (5-HTP, 50–200 mg/kg, given 30 min before). Yawning elicited by apomorphine but not by physostigmine was enhanced by p-chlorophenylalanine (p-CPA, 25–400 mg/kg i.p., given 24 h before). Apomorphine elicited but not physostigmine-elicited yawning was enhanced by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 8 g/rat, given 14 days before into the dorsal raphe). This treatment led to a 35% depletion of serotonin (5-HT) in the striatum. 5-HTP, p-CPA or 5,7-DHT given alone did not elicit yawning. Bilateral, intrastriatal microinjection of apomorphine (1.5 –50 g/site) but not physostigmine (5–50 g/site) elicited yawning. The dose-response curve was also bell-shaped. These results indicate that central serotonergic pathways play an important role in modulating drug-elicited yawning in rats. Send offprint requests to S. Okuyama at the above address     

Antitumor Immunity Induction by Intracellular Hyperthermia Using Magnetite Cationic Liposomes

Induction of antitumor immunity to T-9 rat glioma by intracellular hyperthermia using functional magnetic particles was investigated. Magnetite cationic liposomes (MCLs), which have a positive surface charge, were used as heating mediators for intracellular hyperthermia. Solid T-9 glioma tissues were formed subcutaneously on both femurs of female F344 rats, and MCLs were injected via a needle only into the left solid tumors (treatment side). The rats were then divided into two groups, which received no irradiation, or irradiation for 30 min given three times at 24-h intervals with an alternating magnetic field (118 kHz, 384 Oe). On the treatment side, the tumor tissue disappeared completely in many rats exposed to the magnetic field. The tumor tissue on the opposite side also disappeared completely, even though MCLs were not injected into the right solid tumors. To examine whether a long-lasting and tumor-specific immunity could be generated, the rats that had been cured by the hyperthermia treatment were rechallenged with T-9 cells 3 months later. After a period of transient growth, all tumors disappeared. Furthermore, immuno-cytochemical assay revealed that the immune response induced by the hyperthermia treatment was mediated by both CD8⁺ and CD4⁺ T cells and accompanied by a marked augmentation of tumor-selective cytotoxic T lymphocyte activity. These results suggest that our magnetic particles are potentially effective tools for hyperthermic treatment of solid tumors, because in addition to killing of the tumor cells by heat, a host immune response is induced.     

Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers' non-small cell lung carcinomas.

PURPOSE: Squamous cell carcinoma (SCC) and adenocarcinoma of the lung are currently subject to similar treatment regimens despite distinct differences in histology and epidemiology. The aim of this study is to identify a molecular target with diagnostic and therapeutic values for SCC. EXPERIMENTAL DESIGN: Genes specifically up-regulated in SCC were explored through microarray analysis of 5 SCCs, 5 adenocarcinomas, 10 small cell lung carcinomas, 27 normal tissues, and 40 cancer cell lines. Clinical usefulness of these genes was subsequently examined mainly by immunohistochemical analysis. RESULTS: Seven genes, including aldo-keto reductase family 1, member B10 (AKR1B10), were identified as SCC-specific genes. AKR1B10 was further examined by immunohistochemical analysis of 101 non-small cell lung carcinomas (NSCLC) and its overexpression was observed in 27 of 32 (84.4%) SCCs and 19 of 65 (29.2%) adenocarcinomas. Multiple regression analysis showed that smoking was an independent variable responsible for AKR1B10 overexpression in NSCLCs (P < 0.01) and adenocarcinomas (P < 0.01). AKR1B10 staining was occasionally observed even in squamous metaplasia, a precancerous lesion of SCC. CONCLUSION: AKR1B10 was overexpressed in most cases with SCC, which is closely associated with smoking, and many adenocarcinoma cases of smokers. These results suggest that AKR1B10 is a potential diagnostic marker specific to smokers' NSCLCs and might be involved in tobacco-related carcinogenesis.     

Use of spiral computerized tomography angiography in patients with subarachnoid hemorrhage in whom subtraction angiography did not reveal cerebral aneurysms

OBJECT: Patients with subarachnoid hemorrhage (SAH) in whom angiography does not demonstrate diagnostic findings sometimes suffer recurrent disease and actually harbor undetected cerebral aneurysms. The management strategy for such cases remains controversial, but technological advances in spiral computerized tomography (CT) angiography are changing the picture. The purpose of this prospective study was to examine how spiral CT angiography can contribute to the detection of cerebral aneurysms that cannot be visualized on angiography. METHODS: In 134 consecutive patients with SAH, a prospective search for the source of bleeding was performed using digital subtraction (DS) and spiral CT angiography. In 21 patients in whom initial DS angiography yielded no diagnostic findings, spiral CT angiography was performed within 3 days. Patients in whom CT angiography provided no diagnostic results underwent second and third DS angiography sessions after approximately 2 weeks and 6 months, respectively. Six patients with perimesencephalic SAH were included in the 21 cases. Six of the other 15 patients had small cerebral aneurysms detectable by spiral CT angiography, five involving the anterior communicating artery and one the middle cerebral artery. Two patients in whom initial angiograms did not demonstrate diagnostic findings proved to have a ruptured dissecting aneurysm of the vertebral artery; in one case this was revealed at autopsy and in the other during the second DS angiography session. A third DS angiography session revealed no diagnostic results in 13 patients. CONCLUSIONS: Spiral CT angiography was useful in the detection of cerebral aneurysms in patients with SAH in whom angiography revealed no diagnostic findings. Anterior communicating artery aneurysms are generally well hidden in these types of SAH cases. A repeated angiography session was warranted in patients with nonperimesencephalic SAH and in whom initial angiography revealed no diagnostic findings, although a third session was thought to be superfluous.     

Pulmonary metastasectomy for metachronous metastasis of esophageal cancer after esophagectomy

Background and objective

Pulmonary metastasectomy is a standard therapy for some types of metastatic lesions in the lung. Although the prognosis for esophageal cancer patients with pulmonary metastasis is poor, it has been reported that some post-esophagectomy patients have good prognosis after pulmonary metastasectomy. We investigated the role of resecting pulmonary metastases arising from esophageal cancer at our institution.

Patients and methods

Seven patients with primary squamous cell carcinoma or adenocarcinoma of the thoracic esophagus who underwent resection of metachronous pulmonary metastases at our institution between 2006 and 2012 were identified from a retrospective database. All patients had undergone curative resection of their primary esophageal carcinoma.

Results

Six patients had unilateral and solitary lung metastasis. One patient presented with one metastatic lesion on each side, and he underwent 4 metastasectomy for pulmonary metastasis 3 times. There was no perioperative morbidity or mortality. The disease-free interval after esophagectomy ranged from 191 to 559 days (median, 463 days). Survival after pulmonary metastasectomy ranged from 357 to 3191 days (median, 1803 days). Three patients received systemic chemotherapy before metastasectomy. Currently, 5 patients are alive without evidence of recurrent disease.

Conclusion

Pulmonary metastasectomy may be acceptable as a part of multimodal treatment for solitary metachronous pulmonary metastasis in esophageal carcinoma.

     

Recent decline in hospital mortality among patients with acute myocardial infarction.

BACKGROUND: Many patients with acute myocardial infarction will still die after admission. Recent trends in hospital mortality were analyzed to identify aspects that need improvement. METHODS AND RESULTS: A total of 1,247 patients admitted to Kinki University School of Medicine within 24 h of the onset of infarction were analyzed between 1975 and 2001. The percentage of patients discharged with 100% occlusion decreased gradually from 31.3% during 1975-1982 to 2.1% during 1998-2001, while those with 50% stenosis or less gradually increased from 12.5% to 82.5% during the same period (trends: p < 0.01). The cardiac death rate was 17.1% in 1975-1982, and 7.7% in 1998-2001, showing a significant decrease with time (p < 0.01). This decrease was particularly marked among those admitted within 6 h of the onset of infarction. Death due to cardiac rupture decreased significantly with time (p < 0.001). In contrast, the non-cardiac death rate, amounting to 2.2% on average, did not decline. CONCLUSIONS: Cardiac deaths due to acute myocardial infarction have decreased markedly of late. However, patients must be admitted within 6 h of the onset of infarction to benefit from this improvement. More effort should be made to improve the general care of patients in order to reduce the incidence of non-cardiac death.