Prospective analysis of DNA ploidy, proliferative index and epidermal growth factor receptor as prognostic factors for pretreated uterine cancer.

For the purpose of identifying prognostic factors for pretreated uterine cancer, DNA ploidy, proliferative index (P.I.) and epidermal growth factor receptor (EGFR) expression were analyzed in a large prospective series of 76 cervical cancer and 64 endometrial cancer patients observed for 5 years or more (median 76 months). The frequency of aneuploid cells was 62.0% (44/71) in cervical cancer and 16.7% (10/60) in endometrial cancer. There was no association between DNA ploidy and the clinicopathological findings without clinical stage, in which aneuploid cervical and endometrial cancers were significantly more common among advanced tumors (cervical: p<0. 05, endometrial: p<0.01). The P.I. was significantly higher in the patients with aneuploid tumors (cervical: p<0.05, endometrial p<0. 01). EGFR expression was detected in 56.6% (30/53) in cervical cancer and 59.6% (34/57) in endometrial cancer, and the mean EGFR level was 17.8+/-37.7 and 9.5+/-42.5 fmol/mg. protein, respectively. There was no correlation between EGFR expression and DNA ploidy, P.I. and clinicopathological findings analyzed. Five-year survival rate in patients with aneuploid tumors tended to have a worse outcome in cervical cancer cases (p=0.1003, log-rank test), and was significantly worse in endometrial cancer (p=0.0048, log-rank test). No significant relationship was noted between P.I., EGFR expression and 5-year survival. Cox multivariate analysis showed that DNA ploidy, P.I., and EGFR expression are not association with the risk of death. Our data showed neither DNA ploidy, P.I. nor EGFR expression were independent prognostic factors for pretreated uterine cancer.

[Multi-drug antiemetic treatment and effect of treatment duration of concurrent steroids--for complete control of chemotherapy-induced nausea/vomiting in gynecological cancer].

Antiemetic effect and safety of concurrent administration of ondansetron and other antiemetics (dexamethasone, domperidone and ethyl loflazepate), given for complete suppression of nausea/vomiting, were examined in 46 patients (109 courses) with gynecological cancer receiving single high-dose of cisplatin or carboplatin. As for the delayed emesis, antiemetic effect depending on the steroid treatment duration, given concurrently to ondansetron, was compared. The results were as follows; 1. In 78 courses, anticancer drugs were given concurrently to cisplatin or carboplatin only on Day 1. In the remaining 31 courses, those drugs were concurrently administered up to Day 6 at the longest. 2. Complete suppression (i.e., no onsets) rate of acute emesis was 64.2% (70/109 courses) for nausea, and 84.4% (92/109 courses) for vomiting. 3. When the complete suppression depending on duration of concomitant steroid was examined mainly in patients receiving CAP (cyclophosphamide, adriamycin and cisplatin), higher antiemetic effect, especially in nausea, was observed in those on concomitant steroids for 3 days compared to that for 1 day. 4. The food intake rate improved along with nausea symptoms. 5. No adverse event or laboratory abnormality due to the multi-antiemetic treatment was observed. Based on the above, the efficacy of the antiemetic treatment in this study was confirmed. In delayed emesis, concurrent steroids given for 3 days after chemotherapy were considered effective and were also regarded to improve food intake.

[Effect of intravaginal administration of cisplatin (CDDP) suppositories to uterine cervical cancer--blood and tissue concentrations and the therapeutic effects].

Four patients with cervical cancer (squamous cell carcinoma: two cases of stage Ib, one of stage IIa, adenocarcinoma: one of stage Ib), were treated preoperatively by intravaginal administration of CDDP (20 mg) suppositories with pessary 7 times every other day. The uptake, distribution and antitumor effect of CDDP were investigated. Results were as follows. 1) Serum total platinum (Pt) concentration varied between individual patients. Cmax profile (0.17-0.57 micrograms/ml) of Pt was observed at 12 hours after the total dose of 140 mg administration in all patients. 2) The tissue Pt concentration showed high values in the cervix (average 55.4 micrograms/g), followed by the vagina (13.13), endometrium (3.17), uterine wall (0.64), ovary (0.57), lymph node group: parametrial (1.14), obturator (0.34), inguinal (0.28), external iliac (0.51), internal iliac (0.42) and common iliac (0.54). Para-aortic node value was too low to detect. 3) Colposcopic findings were disappearance of bleeding and reduction of tumor outgrowth. Microscopic findings were degeneration and necrosis of cancer nest from the surface to about 2 mm depth of the cervix. In conclusion, it may be necessary to improve CDDP penetration from the tumor surface for effective local chemotherapy.

[Antiemetic efficacy of the repeated use of granisetron in multiple cycles of anti-cancer chemotherapy].

Twenty-three patients with gynecological cancer who were treated with 85 cycles of cytotoxic chemotherapy containing platinum received intravenous granisetron repeatedly. Granisetron (3 mg/body) was drip-infused twice for each cycle at a 24-hour interval. The antiemetic efficacy was evaluated and compared for each day and each cycle, and analysed using the chi-square and H tests. There were no significant differences between the first cycle and the subsequent second through fifth cycles in the severity of nausea and the frequency of vomiting. The latter tended to increase in the second day of each cycle. These results indicated that granisetron does not decrease in antiemetic efficacy by repeated administration during multiple cycles of anti-cancer chemotherapy.

[Amplified DNA detection of HPV types 16 and 18 DNA in cervical scrapes by polymerase chain reaction].

Cervical scrapes from 43 patients (12 with chronic cervicitis, 13 with dysplasia, 11 with carcinoma in situ and 7 with invasive carcinoma) were examined by the polymerase chain reaction (PCR), to detect the amplified E7 gene of the HPV types 16 and 18 DNA sequence. HPV types 16 and/or 18 DNA were detected in 25 of 43 cases by the PCR (type 16 in 16, type 18 in 8, and both types 16 and 18 in 1). In comparison with the results for histological grades, the positive rate significantly increased as the grade of cervical dysplasia became higher. All cases were also examined with a HPV detection kit, the "Vira Pap" which contains 32P-labeled mixed RNA probes complimentary to HPV types 6, 11, 16, 18, 31, 33, 35 DNA. Six of 18 cases in which HPV DNA were not detected by the Vira Pap were positive for HPV types 16 and/or 18, so that the PCR was a highly sensitive method compared to the Vira Pap. The PCR has some advantages: 1. it requires only a small amount of specimens and 2. paraffin-embedded sections can also be used. We suggest that the PCR is a useful method for the screening and for retrospective investigation of HPV infection.

[In situ hybridization study on the detection of HPV DNA in adenocarcinoma and adenosquamous carcinoma of the uterine cervix].

Human papillomavirus (HPV) types 16 and 18 have been found closely associated with squamous cell carcinoma and related lesions of the uterine cervix. In order to investigate the relationship between HPV and adenocarcinoma and adenosquamous carcinoma of the uterine cervix, formalin-fixed, paraffinembedded tissues prepared from 38 cases consisting of 30 cases of adenocarcinoma and 8 cases of adenosquamous carcinoma were examined for the presence of HPV DNA by in situ hybridization with digoxigenin labeled HPV 6/11, 16, 18 DNA probes. HPV DNA was localized on the nuclei of the cancer cells in adenocarcinoma and adenosquamous carcinoma. HPV DNA was detected in 13 cases (43.3%) of adenocarcinoma and 4 cases (50.0%) of adenosquamous carcinoma, and HPV type 18 DNA was detected in 13 cases (34.2%) of adenocarcinoma and adenosquamous carcinoma. These findings suggest an association between HPV, especially HPV type 18, and adenocarcinoma and adenosquamous carcinoma of the uterine cervix.

[Study on the localization of human papillomavirus DNA in the vulvar disease by means of in situ hybridization].

We investigated human papillomavirus (HPV) DNA of vulvar diseases obtained from 18 cases of condyloma acuminatum, 3 cases of hyperplastic dystrophy without atypia, 4 cases of lichen sclerosus, 4 cases of Bowenoid papulosis, one case of Bowen disease and 8 cases of squamous cell cancer by in situ hybridization with biotinylated HPV 6, 11, 16 and 18 DNA probes. The results of in situ hybridization analysis showed that HPV 6/11 was positive in 94.4% (17/18) of condyloma acuminatum. In 17 cases of HPV 6/11 positive condyloma acuminatum, 3 cases were positive for HPV 16 and one for HPV 18, respectively. HPV 16 was positive in 75.0% (3/4) of Bowenoid papulosis and one case of Bowen disease was positive for HPV 18. In two cases of Bowenoid papulosis which were positive for HPV 16, cervical carcinoma in situ containing HPV 16 DNA sequences was also found during the follow up period. In 8 cases of squamous cell cancer, 2 cases were positive for HPV 18, one for HPV 16 and one for HPV 6/11. All cases of hyperplastic dystrophy without atypia and lichen sclerosus were negative for HPV DNA. Our results suggested HPV is closely associated with vulvar neoplasia.

[Three cases of vulvar bowenoid papulosis: the localization of HPV DNA by in situ hybridization].

Cytological, histological, and molecular biological studies were conducted in 3 cases of vulvar Bowenoid papulosis, using biotinylated HPV DNA probes by in situ hybridization. 1) Cytological findings showed dyskaryotic cells that revealed hyperchromatism with a coarse granular pattern, and a high N/C ratio was observed among the dyskeratotic cells. 2) In 2 cases of Bowenoid papulosis lesions, HPV 16 DNA was detected in the nucleus of the dysplastic cells. 3) In one case of Bowenoid papulosis, a complicated carcinoma in situ of the uterine cervix was observed, and the HPV 16 DNA was found to be positive in both the vulva and cervix.

[In situ hybridization study on the localization of HPV DNA in the precancerous lesions of uterine cervix].

Human papillomavirus (HPV) types 16 and 18 have been found closely associated with cervical cancer. In order to investigate the relationship between HPV DNA and cervical precancerous lesions, we examined the formalin fixed specimens obtained from 22 cases of mild dysplasia, 33 cases of moderate dysplasia and 31 cases of severe dysplasia of the uterine cervix for the presence of HPV 6/11, 16 and 18 DNAs by in situ hybridization using the biotinylated HPV DNA probes. We also followed some HPV DNA positive cases of cervical dysplasia for more than 6 months prospectively. The results of in situ hybridization analysis revealed that HPV DNA was detected in the nuclei of koilocytosis, dysplastic cells and metaplastic cells. HPV 6/11 was positive in 27.3% (6/22) of mild dysplasia and 21.2% (7/33) of moderate dysplasia. On the other hand, HPV 16 positive rate increased with the grade of dysplasia and 36.4% (12/33) of moderate dysplasia, 61.3% (19/31) of severe dysplasia were positive for HPV 16 DNA. Some of the follow-up cases which were positive for HPV 16 DNA were later found to have carcinoma in situ. Our results suggest that HPV type 16 might play an important role in cervical carcinogenesis.

[Detection of human papillomavirus types 16 and 18 DNA sequences in the screening of the cells related with carcinoma in situ of the uterine cervix--application of in situ hybridization for cytologic diagnosis].

In order to investigate the relationship between the presence of human papillomavirus (HPV) DNA and cervical carcinoma, we examined the cervical screening cells as well as the biopsy specimens obtained from 3 cases of severe dysplasia, 13 cases of carcinoma in situ (CIS) and 2 cases of microinvasive carcinoma for the presence of HPV types 6, 11, 16 and 18 DNA by DNA-DNA in situ hybridization using the biotinylated HPV DNA probes. The results of in situ hybridization analysis revealed that HPV 16 DNA sequences were detected in the nuclei of koilocytosis of severe dysplasia and CIS cases. The nuclei of atypical cells obtained from cervical screening cells were positive for HPV 16 or 18 DNA sequences. Two CIS cases were positive for the presence of HPV 16 and 18 DNA sequences. None of them contained HPV 6/11 DNA sequences. Eighteen cervical screening cases were examined and 10 contained HPV 16 DNA sequences and 6 contained HPV 18 DNA sequences. We suggest that the identification of HPV DNA types in cervical screening cells by in situ hybridization might be of diagnostic and prognostic value in early cervical neoplasia.