Hitoo Nakano

Multivariate analysis of the histopathologic prognostic factors of cervical cancer in patients undergoing radical hysterectomy

Three hundred forty‐five patients with invasive carcinoma of the uterine cervix, Stages Ib (211 patients) and II I (134 patients), underwent radical hysterectomy and pelvic lymphadenectomy. The influence of histologic factors including histologic subtype, maximum depth of cervical stromal invasion, degree of stromal invasion, longitudinal tumor diameter, lymph‐vascular space invasion, corpus invasion, parametrial invasion, vaginal invasion, and pelvic lymph node (PLN) metastases on survival were examined by multivariate analysis. Univariate analysis revealed that all the variables except corpus invasion and vaginal invasion were significant in survival (P < 0,05). Among these variables, however, PLN metastases, histologic subtype, and longitudinal tumor diameter were identified as independent and significant prognostic factors by multivariate analysis using Cox regression models. The prognostic index (PI), defined by the model (an indicator of the patients place in the prognostic spectrum), was able to divide the patients into three prognostic groups. The key factors in the definition of these groups were (1) squamous cell carcinoma, small tumor diameter, and no PLN metastases for the good prognostic group and (2) PLN metastasis in two or more node groups, adenocarcinoma with one positive PLN group, or squamous cell carcinoma with one PLN group and large diameter for the poor prognostic group. These prognostic findings could predict the prognosis more precisely than that of clinical staging.

Diffusion-weighted echo-planar MR imaging and ADC mapping in the differential diagnosis of ovarian cystic masses: Usefulness of detecting keratinoid substances in mature cystic teratomas

To elucidate whether apparent diffusion coefficient (ADC) values calculated from echo‐planar diffusion‐weighted MR imaging (EPDWI) are useful in the differential diagnosis of ovarian cystic masses.

Histological classification of ovarian cancer.

 The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.

Clinical Significance of Heparin-Binding Epidermal Growth Factor–Like Growth Factor and A Disintegrin and Metalloprotease 17 Expression in Human Ovarian Cancer

Purpose: Lysophosphatidic acid, which is enriched in the peritoneal fluid of ovarian cancer patients, plays a key role in the progression of ovarian cancer. Lysophosphatidic acid can generate epidermal growth factor receptor (EGFR) signal transactivation involving processing of EGFR ligands by ADAM (a disintegrin and metalloprotease) family metalloproteases. We aimed to investigate the clinical significance of EGFR ligands and ADAM family in the lysophosphatidic acid–induced pathogenesis of ovarian cancer. Experimental Design: We examined the expression of EGFR ligands and ADAM family members in 108 patients with normal ovaries or ovarian cancer, using real-time PCR, immunohistochemistry, and in situ hybridization, and analyzed the clinical roles of these molecules. Statistical analyses of these data were done using the Mann-Whitney test, Kaplan-Meier method, or Spearmans correlation analysis. Results: Large differences in expression were found for heparin-binding EGF-like growth factor (HB-EGF) and other EGFR ligands and for ADAM 17 and other ADAM family members. HB-EGF expression was significantly increased in advanced ovarian cancer compared with that in normal ovaries (P < 0.01). HB-EGF expression was significantly associated with the clinical outcome (P < 0.01). ADAM 17 expression was significantly enhanced in both early and advanced ovarian cancer compared with that in normal ovaries (both P < 0.01), although it had no clinical significance in the progression-free survival. HB-EGF expression was significantly correlated with ADAM 17 expression (γ = 0.437, P < 0.01). Conclusions: Our findings suggest that HB-EGF and ADAM 17 contribute to the progression of ovarian cancer and that HB-EGF plays a pivotal role in the aggressive behavior of a tumor in ovarian cancer.

Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein.

To elucidate the role of P-glycoprotein in human placenta, we examined its expression in placenta, and the transcellular transport and uptake of P-glycoprotein substrates in cultured human placental choriocarcinoma epithelial cells (BeWo cells). The uptake of [(3)H]vinblastine and [(3)H]vincristine into BeWo cells was increased in the presence of a metabolic inhibitor, sodium azide. The basolateral-to-apical transcellular transport of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin was greater than the apical-to-basolateral transcellular transport. In the presence of cyclosporin A, the basolateral-to-apical transcellular transport of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin was significantly increased, and the apical-to-basolateral transcellular transport was decreased. The uptake of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin into BeWo cells was significantly enhanced in the presence of several inhibitors, such as verapamil or mouse monoclonal antibody anti-P-glycoprotein MX-MDR (MRK16) as well as cyclosporin A. Although progesterone significantly enhanced the uptake of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin into BeWo cells, the uptake of [(3)H]progesterone was not affected by these inhibitors. Immunoblot analysis revealed that P-glycoprotein with a molecular weight of 172 kDa was expressed in BeWo cells and isolated trophoblast cells. Furthermore, P-glycoprotein was detected in human placental brush-border membrane vesicles, but not in human placental basolateral membrane vesicles. In conclusion, these data suggest that P-glycoprotein is expressed on the brush-border membrane (maternal side) of human placental trophoblast cells. P-Glycoprotein is considered to regulate the transfer of several substances including vinblastine, vincristine and digoxin from mother to fetus, and to protect the fetus from toxic substances.

Basal Membrane Localization of MRP1 in Human Placental Trophoblast

The placental trophoblast is considered to act as a barrier between mother and fetus, mediating the exchange of various materials across the placenta. ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and multidrug-resistance protein (MRP) are expressed in the placenta and function as efflux transport systems for xenobiotics. In the present study, we aimed to determine the localization of MRP1 in the human placenta in comparison with that of P-gp. Western blotting analysis with human placental membrane vesicles indicated that P-gp and MRP1 are localized on the brush-border membranes and basal membranes, respectively. Immunohistochemical analysis with human normal full-term placenta showed that anti-P-gp monoclonal antibody F4 stained the brush-border side of the trophoblast cells, whereas anti-MRP1 monoclonal antibody MRPr1 stained the basal side. These results confirm that P-gp and MRP1 are located on the brush-border membranes and basal membranes, respectively, of human full-term placental trophoblast. MRP1 was also detected on the abluminal side of blood vessels in the villi. Accordingly, MRP1 may play a role distinct from that of P-gp, which is considered to restrict the influx of xenobiotics into the fetus.

Clinical evaluation of schizophyllan combined with irradiation in patients with cervical cancer: A randomized controlled study

To evaluate the clinical effects of the anti‐tumor polysaccharide Schizophyllan (SPG), a randomized study was done on 220 patients with Stage II or Stage III cervical cancer who had been given irradiation, concomitantly. The tumor‐reducing effect of SPG was significant in patients in either stage. The time to recurrence was longer in SPG‐dosed patients with Stage II cancer, compared with findings in the control group. There was no significant difference in the time to recurrence in patients with Stage III cancer between the SPG and control groups. When comparing the 48‐month survival curve, the survival time of patients with Stage II cancer in the SPG group was significantly longer than in the control group. However, there was no significant difference in the survival rate of patients with Stage III cancer between the SPG‐ dosed and control groups.

Circadian rhythm of plasma atrial natriuretic peptide, aldosterone, and blood pressure during the third trimester in normal and preeclamptic pregnancies

The influence of pregnancy on circadian variations of plasma atrial natriuretic peptide and aldosterone was studied. In those women with normal pregnancies, the mean 24-hour values of atrial natriuretic peptide and aldosterone increased, compared with the levels in normal nonpregnant subjects. In cases of severe preeclampsia, levels of atrial natriuretic peptide were significantly higher than in the other subjects, but aldosterone levels decreased to nearly those seen in the nonpregnant subjects. Atrial natriuretic peptide did not establish a rhythm in normal nonpregnant and pregnant subjects, but in the studies of aldosterone levels, a clear circadian rhythm was evident. In severe cases of preeclampsia, atrial natriuretic peptide established a circadian rhythm similar to that of blood pressure, and the circadian rhythm of aldosterone disappeared. The main characteristic of the rhythm in atrial natriuretic peptide and blood pressure in women showing preeclamptic signs is that the acrophase occurred at midnight. This evidence suggests that in women with symptoms of preeclampsia the load to the atria increases at midnight.

Expression of lysophosphatidic acid receptors and vascular endothelial growth factor mediating lysophosphatidic acid in the development of human ovarian cancer

Lysophosphatidic acid (LPA) receptors including LPA(1), LPA(2), and LPA(3) mediate lysophosphatidic acid signals. We analyzed the expression of LPA receptors, vascular endothelial growth factor (VEGF), and interleukin-8 in 97 patients from normal ovary to ovarian cancer, using reverse transcription polymerase chain reaction. LPA(2), LPA(3), and VEGF expression ratios significantly increased in cancer, compared to those in non-cancerous state (P<0.05). A significant correlation in the expression ratios between LPA(2) or LPA(3) and VEGF was found (gamma=0.617, P<0.0001; gamma=0.431, P<0.001) in patients with cancer. These results suggested that LPA(2) and LPA(3) may be involved in VEGF expression mediated by LPA signals in human ovarian oncogenesis.

Oestradiol-induced relaxation of rabbit basilar artery by inhibition of voltage-dependent Ca channels through GTP-binding protein

1 Effects of oestradiol on the electrical and mechanical properties of the rabbit basilar artery were investigated by use of microelectrode, patch‐clamp and isometric tension recording methods. 2 Oestradiol (10 μm‐100 μm) relaxed arterial tissue pre‐contracted by excess [K]0 solution (30 mM) in a concentration‐dependent manner. In Ca‐free solution, histamine (10 μm) and caffeine (20 mM) each produced a phasic contraction, but oestradiol (10 μm) did not significantly affect their amplitude. 3 Oestradiol (≥ 100 μm) did not change the resting membrane potential of the artery whether in the presence or absence of TEA (10 mM). Action potentials observed in the presence of 10 mM TEA were abolished by oestradiol (100 μm). 4 Oestradiol (1 μm‐100 μm) inhibited the voltage‐dependent Ba current in a concentration‐dependent manner. Oestradiol (100 μm) inhibited the Ba current observed in the presence of nicardipine (1 μm) more than that in the absence of nicardipine (to 31.0% vs 62.0% of control). 5 GTPγS (30 μm) in the pipette enhanced the inhibitory actions of oestradiol on the Ba current. On the other hand, with GDPβS (1 mM) in the pipette, oestradiol failed to inhibit the Ba current. Pertussis toxin (PTX 3 μg ml−1) in the pipette totally prevented the inhibitory action of oestradiol on the Ba current. 6 Oestradiol (≷ 100 μm) had no significant effect on the outward K currents evoked by a membrane depolarization. 7 These results strongly suggest that oestradiol relaxes arterial tissue by inhibition of voltage‐dependent Ca channels and that it inhibits both nicardipine‐sensitive and‐resistant Ca currents via a PTX‐sensitive GTP‐binding protein. The main target of oestradiol among the arterial Ca channels seems to be the nicardipine‐resistant Ca channel, rather than the nicardipine‐sensitive one.