Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer. Cervical Cancer Immunotherapy Study Group

The efficacy of immunotherapy using a streptococcal preparation, OK-432, was evaluated in each clinical stage of uterine cervical cancer. The 382 eligible patients were stratified by clinical stage and presence/absence of surgery. Within each stratum, patient's were randomly allocated to OK-432 treatment or to control treatment. OK-432 significantly inhibited recurrence in patients with stage II cervical cancer; the recurrence-free interval and survival time were remarkably prolonged in patients with stage II disease who underwent surgery. However, OK-432 did not significantly prolong these parameters in patients with stage III disease. Retrospective analyses revealed that in patients with or without lymph node metastases who underwent surgery, the recurrence-free interval and survival time were significantly prolonged by OK-432 treatment. These results indicate that OK-432 is an effective and useful postoperative immunotherapeutic agent for uterine cervical cancer.     

Sialyl Lewis-Xi antigen in patients with gynecologic tumors

Sialyl Lewis-Xi antigen was measured by sandwich radioimmunoassay in sera from patients with various gynecologic tumors: 27 uterine myomas, 117 cervical cancers, 46 endometrial cancers, 54 benign ovarian cysts, and 47 ovarian cancers. Among the patients with uterine malignancies, only a few cases showed serum sialyl Lewis-Xi antigen values in excess of the cutoff limit. On the other hand, among the patients with ovarian cancers, serum sialyl Lewis-Xi antigen was elevated significantly in the following order: clinical stage I (44%), stage II (50%), and stage III (62%). The antigen level also correlated with the effect of treatment. However, serum sialyl Lewis-Xi antigen was elevated in 9% of patients with benign ovarian cysts and in 1.4% of normal volunteers. The lack of tumor specificity of sialyl Lewis-Xi antigen limits its diagnostic value for gynecologic malignancies, but serial measurement of this antigen may be useful in evaluating therapy and monitoring patients.     

Characteristics of Papaver somniferum L. cv. ikkanshu cultivated in Izu

The seeds of Papaver somniferum L. cv. Ikkanshu were sown in November (Autumn sowing: AS) and March (Spring sowing: SS) in a field at Izu Experimental Station for Medicinal Plants of National Institute of Health Sciencs, and both AS and SS plants were cultivated to investigate their growth, opium yield and alkaloid content in the opium. Growing periods from the sowing to the opium harvest were approximately six months for AS plants and three months for SS plants. Sizes of plants and capsules in AS were bigger than those in SS, reflecting their growth period. Opium yields per an are in AS and SS were 212.09 g and 142.03 g, respectively. The opium was able to be collected four times in the AS plants though the SS plants ceased to exude opium after the second incision. Therefore higher yield of opium in AS plants seems to be attributed to an amount of opium in the third and fourth incision. Average morphine content in the total opium was 15.61% in AS plants and 15.04% in SS plants, and the estimated amounts of morphine per an are in AS and SS plants were 33.16 g and 21.38 g, respectively.     

Alteration of the p53 Tumor Suppressor Gene Occurs Independently of K-ras Activation and More Frequently in Serous Adenocarcinomas than in Other Common Epithelial Tumors of the Human Ovary

To clarify the role of the p53 tumor suppressor gene in the development of human ovarian epithelial tumors and to study the association of p53 alterations with K-ras activation, a series of 70 common epithelial ovarian tumors from Japanese patients was studied. These included 31 serous adenocarcinomas, 12 mucinous adenocarcinomas, 5 mutinous tumors of borderline malignancy, 13 endometrioid adenocarcinomas, and 9 clear cell carcinomas. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 14 of 36 (39%) informative cases by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction(PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by SSCP analysis of PCR-amplifled fragments. Mutations were found in 22 of 70 (31%) ovarian tumors, including 1 of 5 mucinous tumors of borderline malignancy. Mutations were subsequently characterized by direct sequencing. Single missense base substitutions were detected in 13 ovarian carcinomas and in one case of mucinous tumor of borderline malignancy. Short (1-8 bp) deletions and insertions were found in 8 cases. Mutations in the p53 gene occurred more frequently in serous adenocarcinomas (14/31, 45%) than in all nonserous types of malignant epithelial tumors combined (7/34, 21%;P=0.032). Point mutations in K-ras were identified by dot blot hybridization analysis of PCR-amplified fragments with mutation-specific oligonucleotides and by direct sequencing. The overall frequency of K-ras mutations was 19/70 (27%).K-ras mutations were found in 12 of 17 (71%) mucinous tumors (8/12 mucinous carcinomas [67%] and 4/5 mucinous tumors of borderline malignancy [80%]), and occurred more frequently than in serous carcinomas (4/31, 13%;P=0.00009) or in all nonmucinous types of ovarian epithelial tumors combined (7/53, 13%; p=0.00002). These data suggest that different combinations of oncogenes and/or tumor suppressor genes may be involved in the genesis and development of histologically distinct categories of common epithelial tumors of the human ovary.     

The anti-tumor arotinoid RO 40-8757 protects bone marrow from the toxic effects of 5-fluorouracil

Combination therapy with 5-Fluorouracil (5-FU) and the arotinoid Ro 40-8757 (mofarotene) of established chemically induced mammary tumors in rats was examined. The cytotoxic drug was administered weekly and Ro 40-8757 was given daily. The dose of Ro 40-8757 used in this study did not have an effect on tumor burden but, in combination with 5-FU, significantly enhanced the reduction in tumor burden and tumor number. In order to determine if Ro 40-8757 had a protective effect on 5-FU-treated animals, several studies were performed with non-tumor-bearing mice. The 5-FU was given once a week for 3 weeks at a dose that was lethal only after the third administration. When this treatment was combined with Ro 40-8757 given 5 times/week, approximately 50% of the mice survived. Examination of the progenitor cell contents of femura and spleens of treated mice indicated that the protective effect of Ro 40-8757 was manifested at the primitive hemopoietic progenitor cell level. Studies with murine bone marrow cells and human breast-cancer cell lines in vitro demonstrated that there was no interaction between the 2 drugs at the cellular level, indicating that the arotinoid does not enhance the ability of cells to metabolize 5-FU. This protective effect of the arotinoid makes it a useful potential partner for combination therapy with 5-FU. © 1994 Wiley-Liss, Inc.     

Evoked otoacoustic emissions in sensorineural hearing impairment: its clinical implications

This study was performed for the purpose of determining whether or not evoked otoacoustic emissions are useful as a clinical test. Two hundred and twenty-six sequences of the emission in response to stimulus tone bursts were averaged. The detection threshold of the emission was elevated in ears of inner ear impairment with profound sensorineural hearing loss, such as inner ear anomaly, mumps deafness, or sudden deafness, but it was not observed in ears of functional deafness. The mean interaural differences of emission threshold were near 35 dB in unilateral inner ear impairments with profound hearing loss. There was a positive correlation between the interaural difference of audiometric threshold and that of emission threshold in sudden deafness ears with various degrees of hearing loss. The incidence of continuous emission, whose duration was longer than 6 msec, was 30% in normal hearing ears and it was close to 90% in ears with bilateral or unilateral dip type hearing loss. The result was verified in a survey of a junior high school brass band. The conclusion is that there is clinical usefulness for the evoked otoacoustic emissions in evaluating cochlear function and in predicting noise susceptibility.     

The clinical significance of serum sialyl Tn antigen levels in patients with gynecologic tumors

In order to estimate the clinical significance of sialyl Tn (STN) antigen, the antigen was measured with an "STN" Otsuka Kit in sera from patients with various gynecologic tumors and healthy women. The antigen in ovarian fluid was also determined. Furthermore, the amount of serum STN antigen was serially checked in the patients with increased serum STN to evaluate the correlation between serum STN and the response to treatment. Results obtained were as follows. 1) Among the patients with uterine myoma, uterine malignancies and benign ovarian tumors, the incidence of increased serum STN antigen was low. 2) Among the patients with ovarian malignancies, serum STN antigen was significantly increased in the following order: Clinical stage I (18%) stage II (22%) stage III (68%). 3) The highest STN value was observed in the cyst fluid from ovarian malignancies. 4) The serum STN concentration was correlated with the effect of treatment. Interestingly, the increase in serum STN preceded the clinical detection of recurrence in one case. Thus STN appears to be a useful marker for monitoring ovarian malignancies.     

Comparison of Incorporation and Extension of Nucleotides in vitro opposite 8-Hydroxyguanine (7,8-Dihydro-8-oxoguanine) in Hot Spots of the c-Ha-ras Gene

DNA templates with 8-hydroxyguanine (7,8-dihydro-8-oxoguanine, oh⁸Gua) at a site corresponding to the first or second position of codon 12 of the c-Ha-ras gene were prepared, and the nucleotides inserted opposite the modified base were compared. The Klenow fragment (KF) of Escherichia coli DNA polymerase I inserted C opposite oh⁸Gua at both positions. Taq DNA polymerase incorporated C and A opposite oh⁸Gua, and the ratio of C to A was higher at the first position than at the second position. DNA polymerase α (pol α) inserted A and C at the first position, and A at the second position of codon 12, indicating that the ratio of C to A was higher at the first position. Moreover, we studied the extensions of bases paired with oh⁸Gua by DNA polymerases with or without 3'-5'exonuclease activity. G and T opposite oh⁸Gua were removed, and subsequently C was inserted by KF. We found that an oh⁸Gua:A pair was recognized by the exonuclease activity of the enzyme and that A was partially subsituted by C. On the other hand, pol α extended only C and A opposite oh⁸Gua. No difference was observed with oh⁸Gua at the two positions. These results indicate that the ratio of nucleotides incorporated opposite oh⁸Gua depends on the sequence context, while there is no particular difference in the extension of base pairs involving oh⁸Gua by DNA polymerases.