Shumpei Matsuura

High Incidence of p53 Gene Mutation in Human Ovarian Cancer and Its Association with Nuclear Accumulation of p53 Protein and Tumor DNA Aneuploidy

Using the poylmerase chain reaction and single‐strand conformation polymorphism analysis, p53 gene mutations were examined in 24 cases of ovarian tumor including 14 ovarian carcinomas and 2 borderline cases of common epithelial type, 7 germ cell tumors, and one stromal tumor. Abnormal bands indicating mutations were detected in 12 (50%) of the cases examined, being present most frequently in common “epithelial” ovarian carcinoma (71%, 10/14). One case each of squamous cell carcinoma originating in a dermoid cyst and anaplastic dysgerminoma were positive for mutation. Direct sequencing confirmed 12 mutations and revealed G→A and G→C nucleotide changes in 5 and 3 cases (42% and 25%), respectively. The mutation was localized at the CpG site of the gene in 3 cases. Immunohistochemical examination of p53 protein in 21 cases and DNA flow‐cytometrical analysis in 17 cases were also performed. Nuclear accumulation of the p53 protein and DNA aneuploidy pattern were detected in 11 (52%) and 9 (53%) cases, respectively. These were significantly correlated with p53 gene mutation (P<0.01 and P<0.05, respectively; Fishers exact test). Neither mutation of the p53 gene, nuclear accumulation of p53 protein nor DNA aneuploidy was detected in borderline cases of common “epithelial” type, typical dysgerminoma and immature teratoma. These results suggest that p53 gene mutation, nuclear accumulation of the protein and the DNA aneuploidy pattern are events occurring almost simultaneously in the progression of ovarian tumors, and that p53 abnormalities seem to be correlated with a high grade of malignancy.

A factor inhibiting ovum capture by the oviductal fimbriae present in endometriosis peritoneal fluid

The cumulus-fimbria interaction was investigated in vitro with endometriosis peritoneal fluid (PF). On the oviductal fimbria of the golden hamster, incubated with endometriosis and nonendometriosis PF and culture medium 199 contained 4% bovine serum albumin (control), was placed the mouse oocyte-cumulus complex at 5-minute intervals for 60 to 70 minutes. Incubation periods until the loss of fimbrial capability of ovum capture (ovum capturability disappearance time [OCDT] ) were 23.3 +/- 2.7 (standard error of the mean), 51.7 +/- 2.9, and 61.3 +/- 0.9 minutes with endometriosis, nonendometriosis PF, and control, respectively. OCDT was significantly decreased with cell-free and ultrafiltrated endometriosis PF containing a molecular size greater than 100,000 (26.0 +/- 2.8 and 26.1 +/- 2.5 minutes, respectively). A factor inhibiting fimbrial capability of ovum capture is present in endometriosis PF.

Modulation of S‐100 genes response to growth conditions in human epithelial tumor cells

Many new members of the S‐100 genes are known to be associated with cell differentiation, malignant transformation, and cell cycle. Of the S‐100 genes examined In the present study, calcyclin, calpactin I light chain and calvasculln were expressed In most human epithellal tumor cells, and their expression levels differed according to various growth conditions. Their transcribed levels differed depending on each cell line, but their expression patterns were similarly changed under growth‐modulatory conditions. Their messenger RNA levels increased parallel to the S phase population of cells, and decreased at G1/G2 phases. In contrast, this expression diminished in tumor cells under growth‐Inhibitory conditions, such as treatment with topolsomerase II inhibitor VP‐16 or phorbol 12‐myristate 13‐acetate.

Allelic Loss of Chromosome 16q in Endometrial Cancer: Correlation with Poor Prognosis of Patients and Less Differentiated Histology

Deletion of certain chromosomal regions can be demonstrated in malignant cells. Chromosome 16q is one of the regions where allelic loss is frequently detected in carcinoma of the breast and many other tumors, suggesting that gene(s) which retard tumor growth may exist here. To elucidate the clinico‐pathological significance of chromosome 16q, loss of heterozygosity (LOH) was investigated using microsatellite polymorphism analysis in 58 patients with endometrial lesions (50 with endometrial carcinoma and 8 who had hyperplasia with or without atypia). When 11 regions of chromosome 16q were examined, LOH was found in 20 patients with carcinoma (40%) and none of the patients with hyperplasia. The tumors of 9 of the 20 patients (45%) showed total loss of 16q, while the others (55%) showed partial deletion. Tumors with LOH were histologically less differentiated than those without LOH (P=0.038, χ2 test). Patients with tumors showing LOH of 16q had a worse prognosis than those without LOH according to Kaplan‐Meier survival analysis (P=0.0158, log‐rank test). In addition, LOH of 16q showed a significant relationship to prognosis by Cox regression analysis. Deletion mapping of 16q demonstrated that two regions (16q22.1 and 16q22.2‐23.1) were frequently involved. Patients with 16q22.1 LOH had a poorer prognosis than those with intact 16q22.1 (P=0.0003, log‐rank test). These findings suggest that gene(s) of which defect is possibly related to the aggressiveness of endometrial cancer are localized on a limited region of 16q that includes 16q22.1.

Gestational Changes in Nitric Oxide Synthase Activity in the Rat Placenta

Objective: To assess the importance of nitric oxide (NO) generated in the placenta on pregnancy, nitric oxide synthase (NOS) activities were measured in the rat placentas of different gestational ages.

Urinary Disturbance after Therapy for Cervical Cancer: Urodynamic Evaluation and β2-Agonist Medication

Abstract: Urinary disturbance frequently develops following therapy for cervical cancer; however, no effective medical treatment has so far been reported. Sixty-five patients who developed urinary disturbance after radiation therapy, radical hysterectomy or radical hysterectomy with radiation therapy for cervical cancer underwent urodynamic assessment. Those who underwent radical hysterectomy with radiation therapy experienced the most severe urine loss, as determined by the pad test. All patients showed markedly reduced bladder compliance. A β2-agonist (mabuterol) significantly improved compliance, bladder capacity and flow rate. It is suggested that medication with mabuterol is a potential novel approach to the treatment of urinary disturbance after therapy for cervical cancer.

Patterns of failure and survival in locally advanced carcinoma of the uterine cervix treated with high dose-rate intracavitary irradiation system.

We retrospectively analyzed 71 patients with locally advanced carcinoma of the uterine cervix treated by irradiation using high dose-rate intracavitary brachytherapy between 1978 and 1985. Seven patients were Stage IIIa, 46 Stage IIIb, and 18 Stage IVa. Five-year survivals for Stage IIIa, IIIb, and IVa were 71.4, 60.9, and 16.7%, respectively. An analysis of patterns of failure demonstrated that loco-regional recurrences were observed in 1 (14.3%) for Stage IIIa, 6 (13.0%) for Stage IIIb, and 9 (50.0%) for Stage IVa. The incidence of recurrence outside the pelvis observed in Stage IIIb patients (7 para-aortic nodes, 5 distant metastases) was much higher than that of local recurrence. Five patients (7.0% of the total: 1 with Stage IIIa, 3 with Stage IIIb, 1 with Stage IVa) required surgery to manage the complications. These data suggest that a high dose-rate intracavitary irradiation system is an effective tool for the treatment of cervical cancer. Further efforts to control metastatic lesions outside the pelvis are required for patients with Stage IIIb. To increase a loco-regional control rate for patients with Stage IVa disease, it is important to give additional treatment such as chemotherapy in conjunction with radiation therapy.

Results of the combination of external-beam and high-dose-rate intracavitary irradiation for patients with cervical carcinoma

We retrospectively analyzed 220 patients with squamous cell carcinoma of the uterine cervix treated by the combination of external-beam and high-dose-rate intracavitary brachytherapy between 1978 and 1986. Five-year survivals for Stage Ib (n = 15), IIa (n = 18), IIb (n = 107), IIIb (n = 50), and IVa (n = 18) were 72.3, 88.9, 68.9, 64.0, and 16.7%, respectively. The incidences of recurrence outside the pelvis in Stage IIb and IIIb patients (15.0 and 24.0%) were higher than those of local recurrences (10.3 and 12.0%). Eighteen patients (8.2% of the total) had serious intestinal complications. These serious complications were closely correlated with the external-beam dosages. External-beam therapy was performed at 1.8-2.0 Gy/day, and high-dose-rate brachytherapy using a remotely controlled afterloading system (RALS) was performed once a week with 6.0-7.5 Gy at points A/fraction. Treatment dosages to the whole pelvis (WP), with central shieldings (CS), and with RALS according to FIGO stage were as follows: Stages Ib, IIa, 30-40 Gy (WP) plus 24-30 Gy (RALS); Stages IIb, IIIb, 40 Gy (WP) plus 10-20 Gy (CS) plus 24-30 Gy (RALS); Stage IVa, 40-50 Gy (WP) plus 10-20 Gy (CS) plus 20-30 Gy (RALS). From these data, the combination of external-beam and high-dose-rate intracavitary irradiation is an effective therapy for cervical cancer. It is also suggested that an additional combined chemotherapy is necessary to control metastic lesions outside the pelvis for Stages IIb and IIIb.

ENCEPHALOCELE, POLYCYSTIC KIDNEYS, AND POLYDACTYLY WITH OTHER DEFECTS: A Necropsy Case of Meckel Syndrome and a Review of Literature

Meckel syndrome, which is diagnosed by 2 of 3 main congenital malformations such as an occipital encephalocele, polycystic kidneys, and polydactyly, is an autosomally inherited recessive disease. We have experienced a case of Meckel syndrome and performed necropsy. Necropsy findings revealed multiple congenital malformations with occipital meningo‐encephalocele and agenesis of the cerebellum, 6 digits on the hands and feet, polycystic kidneys. The criteria of Meckel syndrome is still unclear. We propose that the diagnosis of this syndrome may be accompanied by the presence of all triad of main malformations. Ninety four cases satisfying this criteria have been reported in the world literature. Several discussion were made from a review of the literature.

Serum Platelet-Activating Factor Acetylhydrolase Activity in Normal Pregnancy and Preeclampsia

Objective: The aim of this study was to elucidate the roles of platelet-activating factor acetylhydrolase (PAF-AH) in normal and hypertensive pregnancies.Method: Changes in serum PAF-AH activity were investigated in 13 nonpregnant women, 168 normal pregnant women, 11 women in normal puerperium, and 35 pregnant women with preeclampsia (mild: 28, severe: 7). Serum PAF-AH activity was measured by the method of Stafforini et al.Results: The serum PAF-AH activity of normal pregnant women between 5 and 34 weeks gestation was significantly lower than that of nonpregnant women, increasing after 34 weeks gestation and returning to nonpregnant levels within 1 month after delivery. In the pregnant women with mild preeclampsia at 28-41 weeks gestation, serum PAF-AH activity (28.0 ± 1.0 nmol/ min/mL, mean ± SEM, n = 28) was significantly (P < 0.01) higher than that in gestational-age-matched normal pregnant women (21.3 ± 0.8 nmol/min/mL, n = 73). However, in the pregnant women with severe preeclampsia, the activity (1...