Exposure to 1-bromopropane causes ovarian dysfunction in rats.

Although 1-bromopropane has been used in chemical and electronic industries as an alternative to ozone layer-depleting solvents, its toxicity on female reproductive organs has not been fully elucidated. The aim of this experiment was to determine the effect of 1-bromopropane on female reproductive function in rats. Forty female Wistar rats were divided into four equal groups. Each group was exposed daily to 0, 200, 400, or 800 ppm of 1-bromopropane for eight h a day. After exposure for 7 weeks, all rats in the 800-ppm group became seriously ill and were sacrificed during the 8th week. The other dose groups were exposed for 12 weeks. In the 800-ppm group, but not in the other two exposed groups, body weight was significantly less than the control at each time point from 2 to 7 weeks after the beginning of exposure. Tests of vaginal smears showed a significant increase in the number of irregular estrous cycles with extended diestrus in the 400- and 800-ppm groups. Histopathological examination of the ovary showed a significant dose-dependent reduction of the number of normal antral follicles and a decrease in the number of normal growing follicles in the 400-ppm group. No significant change was found in plasma concentrations of LH or FSH in any group when compared with the control. Our results indicate that 1-bromopropane can induce a dose-dependent ovarian dysfunction in nonpregnant female rats associated with disruption in follicular growth process.     

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.     

Alcohol consumption, smoking, and subsequent risk of colorectal cancer in middle-aged and elderly Japanese men and women: Japan Public Health Center-based prospective study.

Few studies have examined the association of alcohol consumption and cigarette smoking with colorectal cancer in Asian populations whose genetic susceptibility to these factors are different from Western populations. We investigated this association and the joint effect of these factors, and estimated the population-attributable fraction to clarify the public health impact on a Japanese population, based on a prospective study. We analyzed the 10-year (cohort I) and 7-year (cohort II) follow-up data of the Japan Public Health Center-based prospective study on cancer and cardiovascular disease, derived from 90,004 (42,540 male and 47,464 female) middle-aged and elderly Japanese. We identified 716 (457 in men and 259 in women) newly diagnosed cases of colorectal cancer. Both alcohol consumption and smoking were clearly associated with colorectal cancer in men, after adjusting for age, family history of colorectal cancer, body mass index, and physical exercise. Regular heavy drinking of 150 g/week or more of ethanol showed a statistically significant increased risk compared with nondrinkers: relative risks (RRs) were 1.4 [95% confidence interval (CI), 1.1-1.9] for 150-299 g/week and 2.1 (95% CI, 1.6-2.7) for 300 g/week or more. On the contrary, regular ethanol consumption was not associated with colorectal cancer (RR, 0.7; 95% CI, 0.4-1.1) in women. In terms of smoking, the RRs were 1.4 (95% CI, 1.1-1.8) for current smokers and 1.3 (95% CI, 0.98-1.7) for ex-smokers compared with never-smokers in men. The risk of smoking in women was similar to that in men, although not statistically significant. The colorectal cancer risk with 300 g/week or more of ethanol in current smokers was estimated at 3.0 (95% CI, 1.8-5.1) compared with nondrinkers among nonsmokers in men. Colorectal cancer attributable to alcohol consumption or smoking was estimated to be 46%. In conclusion, approximately half of the colorectal cancer cases may be preventable by tobacco and alcohol controls in middle-aged and elderly Japanese men.     

Carotid Resection and Reconstruction for Advanced Cervical Cancer

Patients with advanced cervical cancers often have direct invasion of their carotid arteries. The prognosis for these patients with nonsurgical therapy is extremely poor. Because complete tumor removal is the only therapy that can offer these patients a chance for cure, carotid resection should be performed. We performed carotid resection and reconstruction on nine patients with advanced cervical cancers. Of these patients, none suffered from severe neurologic postoperative complications such as permanent hemiplegia. Three of the nine patients have been disease free for more than 24 months. These three patients would not have survived without carotid resection. Further study will show the usefulness of carotid resection and reconstruction in decreasing the morbidity and mortality in patients with cervical cancer involving the carotid artery.     

Seven-year survivor with malignant melanoma of the anus without radical surgery

We report a case of a long-term survivor with malignant melanoma of the anus who did not undergo radical surgery. A 71-year-old woman who presented with anal bleeding and anal tumor underwent an excisional biopsy in September 1985. The biopsy specimen was a lobulated, polypoid, pigmented mass 2 cm in diameter, that had been located on the anterior wall of the anus. A satellite nodule 7 mm in diameter was found on the left wall of the anus at the level of the dentate line. Both tumors were histologically diagnosed as malignant melanoma. The primary tumor was 6 mm thick. Melanoma cells were present microscopically at the cut end of the rectum. Because of her history of ischemic heart disease, the patient rejected our recommendation that she undergo radical surgery, and received 10 courses of carboplatin 20 mg intramuscularly and OK-432 10 K.E. (Klinische Einheit) intradermally every week. A single, pigmented metastatic inguinal lymph node developed and was excised in June 1987. A recurrent tumor was detected in the rectum in October 1992, so again we recommended radical surgery. The patient rejected radical surgery again, and received 12 courses of carboplatin 10 mg intramuscularly every 2 weeks. She died of disease at home in July 1993 after surviving for 7 years and 10 months. An autopsy was not performed. This case shows that local excision of the primary lesion may be appropriate to preserve the quality of life of patients with early-stage malignant melanoma of the anus.     

Plasticity of central monoaminergic systems during aging]

The locus coeruleus (LC), located within the caudal pontine central gray, is composed of noradrenaline-containing neurons. The axons of these neurons form extensive collateral branches that project widely to many brain sites. The function of the LC is still unclear at present, however, LC neurons are known to exhibit marked axonal regeneration and sprouting in response to brain damage. We investigated the age-related changes in noradrenergic innervations of the frontal cortex, using in vivo electrophysiological techniques and immunohistochemistry. While noradrenergic innervations gradually decreased with age in the frontal cortex, a high degree of sprouting occurred in the LC axon terminals in middle age. Neither the electrophysiological properties of LC neurons nor NA levels in the frontal cortex changed with age. These findings suggested that the LC neurons preserve a strong capacity to remodel their axon terminals even in the aging brain. Exogenous brain-derived neurotrophic factor (BDNF) infusion caused a marked increase in the density of noradrenergic axon in the aged brain, but no trophic action of BDNF was observed in the young or middle-aged brain. The result suggests that BDNF is necessary for the maintenance of noradrenergic innervations in the aged brain.     

Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

PURPOSE: To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. PATIENTS AND METHODS: We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. RESULTS: EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). CONCLUSION: EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.