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Biomedical subjects

R Fujiwaki

Publications and source records attributed to R Fujiwaki.

At least 19 recordsLinked to original sources
PubMed2000

Gene expression for dihydropyrimidine dehydrogenase and thymidine phosphorylase influences outcome in epithelial ovarian cancer.

PURPOSE: Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine salvage enzyme responsible for degradation of thymine, which is produced from thymidine by thymidine phosphorylase (TP). Our purpose was to determine whether DPD affects prognosis in patients with epithelial ovarian cancer and how the two enzymes may interact in such effects. PATIENTS AND METHODS: DPD gene expression was analyzed by reverse transcription-polymerase chain reaction in 27 samples from normal ovaries and the 85 epithelial ovarian cancers previously studied with regard to TP gene expression. RESULTS: DPD gene expression was significantly lower in epithelial ovarian cancers than in normal ovaries (P: <.0001), whereas TP gene expression and the ratio of TP to DPD gene expression (TP:DPD) were significantly higher in epithelial ovarian cancer (P: <.0001 for both). In patients with epithelial ovarian cancer, DPD gene expression and the TP:DPD ratio did not significantly correlate with any clinicopathologic factors. Patients with a high TP:DPD ratio (higher than the median) had significantly poorer outcomes than those with lower ratios (P: =.0002). The difference in survival between groups with high and low TP:DPD ratios was greater than the difference between groups with high and low TP gene expression. Multivariate analysis showed the TP:DPD ratio to be the independent prognostic factor (P: =.0002). In tumors with high TP gene expression, low DPD gene expression significantly correlated with poor survival (P: =. 04). CONCLUSION: Downregulation of DPD gene expression may enhance the negative prognostic effect of high TP gene expression in patients with epithelial ovarian cancer. Certain newly available chemotherapeutic choices may take the TP:DPD ratio into consideration.

Adult↗
PubMed2000

Expression of thymidine phosphorylase in epithelial ovarian cancer: correlation with angiogenesis, apoptosis, and ultrasound-derived peak systolic velocity.

OBJECTIVE: The objective of this study was to determine whether the expression of thymidine phosphorylase (TP) by epithelial ovarian cancer cells correlates with the density of microvessels within the tumor, apoptotic index (AI) within the tumor cells, and ultrasound-derived blood flow. METHODS: Color Doppler imaging and pulsed Doppler spectral analysis ultrasonography were used to scan 44 patients with an overt ovarian mass immediately before laparotomy. Sections of malignant tumors were analyzed for the cellular expression of TP and the intratumoral density of microvessels by immunohistochemistry using antibodies to TP and factor-VIII-related antigen, respectively. Moreover, AI was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling methods. RESULTS: Forty-four epithelial ovarian cancers were studied (6 low malignant potential, 15 serous cystadenocarcinoma, 9 mucinous cystadenocarcinoma, 8 endometrioid adenocarcinoma, 4 clear cell carcinoma, and 2 malignant Brenner tumors); 19 were Stage I, 6 Stage II, 15 Stage III, and 4 Stage IV. Fourteen tumors (32%) were classified as being TP positive. The proportion of Stage I tumors that was TP positive (16%) was significantly lower (P = 0.022) that the corresponding value for Stages II-IV (44%), although the values for microvessel count, AI, and peak systolic velocity (PSV) were similar. AI was significantly lower in TP-positive tumors than in TP-negative tumors (P = 0.015). The PSV was significantly higher in TP-positive tumors (P = 0.02). There was a significant correlation between the microvessel count and the PSV (r = 0.34, P = 0.024). Moreover, AI was significantly inversely related to the PSV (r = 0. 35, P = 0.023). The PSV in a subgroup with a high microvessel count and low AI was significantly higher than that in a subgroup with a low microvessel count and high AI (P = 0.0006). These findings significantly associated with TP expression (P = 0.024). CONCLUSIONS: The intratumoral PSV, as determined by color Doppler imaging and spectral analysis, might reflect the coordination of angiogenesis and apoptosis associated with TP expression in epithelial ovarian cancer.

Adult↗
PubMed2000

Expression of the adrenomedullin gene in epithelial ovarian cancer.

Adrenomedullin (AM) gene expression was analysed in 60 cases of epithelial ovarian cancer, (29 serous, 14 mucinous, 13 endometrioid, three clear cell, and one undifferentiated) using reverse transcription-polymerase chain reaction (RT-PCR); 10 of the cases were of low malignant potential; 25 were stage I; three were stage II; 27 were stage III; and five were stage IV. The level of AM gene expression was described in terms of the relative yield of the AM gene to the beta2-microglobulin gene. AM gene expression ranged from 0.04 to 1.57 (median 0.36). The association between histological grade and AM gene expression was significant (P: = 0.027), however, the association with other clinico-pathological features, i.e. patients' age at diagnosis, stage of disease, residual tumour mass after initial surgery, and histological subtype were not significant. Survival data were available for all patients and univariate Cox regression analysis showed that the AM gene expression was significantly associated with a poor prognosis (P: = 0.019). Immunohistochemical studies showed that AM was localized in the outer cell membrane or the cytoplasm of the carcinoma cells and in the endothelial cells of the tumour stroma. The AM gene expression level may play a key role in the biology of epithelial ovarian cancer and may define a more aggressive tumour phenotype.

Adrenomedullin↗
PubMed2000

Expression of TP and TIE2 genes in normal ovary with corpus luteum and in ovarian cancer: correlation with ultrasound-derived peak systolic velocity.

Transvaginal colour and pulsed Doppler ultrasonography analyses of blood flow velocity have indicated that intra-tumoral peak systolic velocity (PSV) is a good indicator of ovarian malignancy. Therefore, we examined whether there was an association between the expression of angiogenic genes, e.g. thymidine phosphorylase (TP) and TIE2 and the PSV of blood flow in normal and cancerous ovaries. Initially, 40 patients were examined by transvaginal ultrasonography and 23 ovaries were surgically removed; 14 were normal with corpora lutea (CL) and nine showed ovarian cancer. The ovarian tissue was dissected according to areas of high blood velocity and gene expression was examined using the reverse transcriptase-polymerase chain reaction (RT-PCR). No significant differences were found between PSV in the normal ovary with CL and ovarian cancer (P = 0.95). TP gene expression was significantly higher in ovarian cancer than in normal ovary with CL (P = 0.02), while TIE2 gene expression was not significantly different (P = 0.186). There was a significant correlation between TIE2 gene expression and PSV in the normal ovary with CL (r = 0.633, P = 0.015), while TP expression was significantly correlated with the PSV in ovarian cancer (r = 0.757, P = 0.018). These results indicate that there is a biological difference between physiological and pathological angiogenesis, TIE2 having a physiological role and TP being involved in pathological angiogenesis.

Adult↗
PubMed2000

Thymidylate synthase expression in epithelial ovarian cancer: relationship with thymidine phosphorylase expression and prognosis.

OBJECTIVE: Thymidylate synthase (TS) and thymidine phosphorylase (TP) are important enzymes involved in the de novo DNA synthesis and the salvage pathways for pyrimidine, respectively. Our purpose was to determine whether the gene expression of TS together with TP correlate with prognosis in epithelial ovarian cancer. METHODS: TS gene expression was analyzed by reverse transcription-polymerase chain reaction in 20 samples from normal ovaries and 56 epithelial ovarian cancers previously studied regarding TP gene expression. TS and TP protein localization was examined by immunohistochemistry. RESULTS: TS gene expression was significantly higher in epithelial ovarian cancer than in normal ovaries (p = 0.001). In patients with epithelial ovarian cancer, TS gene expression did not correlate with patient age, clinical stage, histologic type, or histologic grade. High TS gene expression (> median) significantly correlated with a poorer survival (p = 0.02). No significant correlation between TS and TP gene expression and different immunoreactivity patterns were found. Combined analysis of TS and TP gene expression demonstrated that the relative risk of death for tumors with high TS and high TP expression was greater than that for either only high TS or high TP gene expression (p = 0.002). CONCLUSION: TS and TP combined may indicate a poor prognosis for patients with epithelial ovarian cancer.

Adult↗
PubMed1999

Bilateral granulosa cell tumor in a patient with blepharophimosis syndrome.

Blepharophimosis syndrome is a rare, autosominal, dominant ocular disorder and has been reported to be associated with ovarian dysfunction and premature menopause. We report a case of bilateral granulosa cell tumor associated with blepharophimosis syndrome. The combination of the long-term hypergonadotrophism and oocyte depletion associated with blepharophimosis syndrome may have contributed to the pathogenesis of the granulosa cell tumors. In female patients with blepharophimosis syndrome, close gynecologic surveillance should be instituted.

Aged↗
PubMed1999

Expression of the thymidine phosphorylase gene in epithelial ovarian cancer.

Thymidine phosphorylase (TP) is associated with angiogenesis and the progression of solid tumours. High intracellular levels of this enzyme indicate increased chemosensitivity to pyrimidine antimetabolites. TP gene expression in 56 cases of epithelial ovarian cancer (27 of serous, 10 mucinous, 12 endometrioid, five clear cell and two undifferentiated) were analysed by polymerase chain reaction of RNA after reverse transcription. These included eight of low malignant potential. Twenty were stage I, four stage II, 27 stage III and five stage IV. The level of TP gene expression was presented by the relative yield of the TP gene to the beta2-microglobulin gene. TP gene expression ranged from 0.19 to 5.38 (median 0.93). The value of TP gene expression in stage III-IV was significantly higher than that of TP gene expression in stage I-II (P = 0.0005). Histological grade significantly associated with TP gene expression (P = 0.008), but histological subtype did not (P = 0.166). A follow-up study of 34 cases after complete resection of the primary tumours by surgical operation was performed. TP gene expression of the cases with recurrence showed significantly higher levels compared to cases without recurrence (P = 0.049). Survival data were available for 47 of the 56 patients. The prognosis of the patients with high TP gene expression (equal to, or greater than, median) was to be significantly worse than patients with low TP gene expression (less than median) (P = 0.021). The TP gene expression level may play one of the key roles in the biology of ovarian epithelial cancer and define a more aggressive tumour phenotype. A new therapeutic intervention mediated by TP protein activity is anticipated.

Adult↗
PubMed1999

Thymidine phosphorylase expression in progression of cervical cancer: correlation with microvessel count, proliferating cell nuclear antigen, and apoptosis.

AIMS: To determine how epithelial and stromal thymidine phosphorylase expression affects angiogenesis, rapid tumour growth, and decreased apoptotic activity in cervical cancer at varying stages of progression. METHODS: Epithelial and stromal thymidine phosphorylase expression, the microvessel count (reflected by factor VIII related antigen), and proliferating cell nuclear antigen (PCNA) were assessed immunohistochemically in 25 specimens of normal cervical epithelium, 35 of carcinoma in situ (CIS), 34 of microinvasive carcinoma, and 34 of invasive cervical squamous cell carcinoma. Apoptosis was evaluated by the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labelling (TUNEL) method. The relation of epithelial and stromal thymidine phosphorylase expression to microvessel count, PCNA index, and apoptotic index was examined. RESULTS: Epithelial and stromal thymidine phosphorylase expression progressively increased along a continuum from normal epithelium to invasive squamous cell carcinoma. Epithelial and stromal thymidine phosphorylase expression showed a significant positive correlation with microvessel counts. Within each histological stage, CIS cases with high stromal thymidine phosphorylase expression, invasive squamous cell carcinoma cases with high epithelial thymidine phosphorylase expression, and microinvasive carcinoma cases with high thymidine phosphorylase expression in both epithelium and stroma had a significantly higher microvessel count. High epithelial thymidine phosphorylase expression was associated with a significantly higher PCNA index in CIS and microinvasive carcinoma, but not in invasive squamous cell carcinoma. No significant correlation was seen between apoptotic index and either epithelial or stromal thymidine phosphorylase expression or microvessel count. CONCLUSIONS: Epithelial and stromal thymidine phosphorylase expression may combine to promote angiogenesis during progression of cervical cancer, and epithelial thymidine phosphorylase expression may stimulate tumour cell proliferation in the early stages.

Apoptosis↗
PubMed1999

Prognosis of patients with stage IIIb-IVa squamous cell carcinoma of the cervix following intra-arterial neoadjuvant chemotherapy.

Our purpose was to determine the long-term prognosis in patients with stage IIIb-IVa squamous cell carcinoma of the cervix who were treated with intra-arterial neoadjuvant chemotherapy (NAC), and to analyze factors related to prognostic value. We assessed the disease-free survival of 21 patients with FIGO stage IIIb-IVa squamous cell carcinoma of the cervix treated with intra-arterial NAC (cisplatin 70 mg/m2 and peplomycin sulfate 30 mg/m2) followed by irradiation therapy. Before chemotherapy, five factors (age, clinical stage, histologic type, parametrial involvement and serum level of SCC) were evaluated for their correlation with disease-free survival. The absolute 5-year disease-free survival rate for the entire group was 52%, with a median follow-up time in disease-free survivors of 87 months. Among the prognostic factors, age was the only one to be significantly correlated with disease-free survival; older (> 60 years) patients showed a significantly better disease-free survival rate than did younger (< 60 years) patients (p < 0.05, log-rank test). The absolute 5-year disease-free survival rate was 69% for older patients and 25% for younger patients. Univariate Cox's proportional hazard model also demonstrated that age was a significant prognostic factor as a continuous variable (p < 0.01). Intra-arterial NAC thus appeared to be effective in treating older patients with stage IIIb-IVa squamous cell carcinoma of the cervix.

Adult↗
PubMed1999

Co-expression of vascular endothelial growth factor and thymidine phosphorylase in endometrial cancer.

OBJECTIVE: To examine expression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) together with microvessel count in endometrial cancer, and to investigate the relationship with clinicopathological and biological factors. METHODS: VEGF expression, TP expression, the microvessel count (factor VIII-related antigen positive cells), bcl-2 expression, proliferating cell nuclear antigen (PCNA) index, and p53 expression were determined in 50 resected endometrial cancer specimens, using immunohistochemistry. The relationship between VEGF and TP expression and correlation between expression and microvessel count were also given attention. These 3 factors were analyzed with regard to clinicopathological factors, bcl-2 expression, PCNA index, and p53 expression. RESULTS: Staining status of VEGF and TP was identical in 37 (74%) of 50 tumors, the correlation being statistically significant (p < 0.01). Combined analysis of VEGF and TP status showed that tumors which were VEGF-positive and/or TP-positive had a significantly higher microvessel count than did tumors which were both VEGF-negative and TP-negative (p < 0.001 and p < 0.05, respectively). TP expression correlated with bcl-2 expression, and VEGF expression inversely correlated with the PCNA index. Although clinical stage (p < 0.01), PCNA index (p < 0.01), and p53 expression (p < 0.01) significantly correlated with disease-free survival, neither VEGF/TP expression nor microvessel count contributed to prognostic estimates. CONCLUSIONS: VEGF and TP may cooperatively promote angiogenesis in endometrial cancer, but these expressions may have limited additional prognostic value.

Adult↗
PubMed1998

Immunohistochemical expression of thymidine phosphorylase in human endometrial cancer.

OBJECTIVE: To investigate correlations between the expression of thymidine phosphorylase (TP) by endometrial cancer cells and the density of microvessels within the tumor, the clinicopathologic features, and the prognosis. METHODS: We examined tumor specimens obtained from 46 patients with endometrial cancer (9 FIGO stage IA, 16 stage IB, 8 stage IC, 1 stage IIA, 6 stage IIB, and 6 stage IIIC). The cellular expression of TP and the intratumoral density of microvessels were determined by immunohistochemistry using monoclonal antibodies to TP and factor VIII-related antigen, respectively. We investigated the relationship between the cellular expression of TP and the following factors: clinicopathologic features (menopausal status, histologic type, tumor size, histologic grade, myometrial invasion, cervical invasion, and metastasis), the microvessel count, and the disease-free survival period. RESULTS: Of the 46 tumors, 19 (41%) were TP-positive. The microvessel count was significantly higher in TP-positive tumors than in TP-negative tumors (P = 0.01, Mann-Whitney U test). There was no significant correlation between TP expression and clinicopathologic features, and there was no significant difference in the disease-free survival period between patients with TP-positive tumors and patients with TP-negative tumors. CONCLUSION: TP expression was not correlated with clinicopathologic features or prognosis, but was associated with an increased density of microvessels in endometrial cancer. These findings suggest that TP may play an important role in angiogenesis and may be involved in the tumorigenesis of endometrial cancer.

Adult↗
PubMed1997

Decrease in tumor volume and histologic response to intraarterial neoadjuvant chemotherapy in patients with cervical and endometrial adenocarcinoma.

Our purpose was to evaluate the utility of clinicopathological and biological markers prior to treatment in predicting the immediate response to chemotherapy in cervical and endometrial adenocarcinomas. Twelve patients with locally advanced cervical adenocarcinomas and 16 patients with endometrial adenocarcinomas received intraarterial neoadjuvant chemotherapy (NAC) consisting of cisplatin and doxorubicin before surgical resection. The decrease in tumor volume on magnetic resonance imaging (MRI) ([tumor volume before NAC - tumor volume after NAC]/tumor volume before NAC x 100) and the histologic response to NAC were assessed. Five factors prior to NAC (nuclear grade, pretreatment tumor volume, PCNA index, p53 protein expression, and DNA ploidy) were analyzed for correlation with the decrease in tumor volume and histologic response in cervical and endometrial adenocarcinoma, respectively. In cervical adenocarcinoma, patients with higher PCNA index tumor (> or = 40.2%) showed a significantly greater decrease in tumor volume than those with lower PCNA index (P < 0.05). In patients with endometrial adenocarcinoma, those with a smaller tumors (< 30.3 cm3) showed a significantly greater decrease than those with a larger tumors (P < 0.001). Tumors with higher PCNA index (> or = 31.5%) and negative p53 protein expression appeared to respond better than other tumors, but the difference was not statistically significant. Nuclear grade and DNA ploidy were not correlated with decrease in tumor volume either in cervical adenocarcinoma or in endometrial adenocarcinoma. Four cases of effective histologic response (2 complete responses [no microscopic residual tumor] and 2 marked responses [no macroscopic residual tumor]) were noted only in patients with endometrial adenocarcinoma who had a smaller tumor, higher PCNA index, and negative p53 protein expression. Pretreatment tumor volume and PCNA index were the only significant predictive factors (P < 0.05). Results suggest that the PCNA index in cervical and endometrial adenocarcinomas and the pretreatment tumor volume in endometrial adenocarcinoma appeared to be potentially useful in predicting the immediate response to the chemotherapy.

Adenocarcinoma↗
PubMed1997

Elevation of serum interleukin-1 receptor antagonist levels in women with gynaecological cancers.

This study included 15 patients with gynaecological cancers (7 with cervical cancer, 6 with endometrial cancer, and 12 with ovarian cancer); 7 with benign gynaecological disorders (5 with benign ovarian tumour and 2 with uterine myoma); and 10 healthy women as a control group. Serum interleukin-1 receptor antagonist (IL-1 ra) levels in patients with gynaecological cancer were significantly higher than those in patients with benign gynaecological disorders (P = 0.04) and in healthy controls (P = 0.0009). IL-1 ra may play an important role in host immune responses in local and general environments against gynaecological cancers.

Endometrial Neoplasms↗
PubMed1997

Interleukin-4, interleukin-10, and soluble tumor necrosis factor receptors in cord blood.

OBJECTIVE: We assessed cord blood for levels of interleukin-4 (IL-4), interleukin-10 (IL-10), and p55 (sTNFR-I) and p75 (sTNFR-II) soluble tumor necrosis factor receptors. STUDY DESIGN: Umbilical cord IL-4, IL-10, tumor necrosis factor alpha (TNF alpha), sTNFR-I, and sTNFR-II were measured in 21 normal appropriately grown newborns delivered vaginally (normal pregnancy), and 3 abnormal pregnancies (1 preterm delivery, 1 premature rupture of membranes with chorioamnionitis, and 1 abruptio placentae with fetal and neonatal distress). Umbilical cord arterial blood pH and PO2 were also measured. RESULTS: The TNF alpha, sTNFR-I, and sTNFR-II were detectable in all cord blood samples in normal pregnancies. IL-4 was detected in 10 of 21 samples (47.6%), and IL-10 was undetectable in normal pregnancies. IL-10 could be detected in the cases with chorioamnionitis and abruptio placentae. Soluble tumor necrosis factor receptors in the case with preterm delivery and the case with abruptio placentae were elevated compared with the levels in control samples. CONCLUSION: Both the p55 and p75 soluble tumor necrosis factor receptors are physiologic constituents of term cord blood. An immunosuppressive role of IL-10 and a protective role of soluble tumor necrosis factor receptors are suggested in abnormal pregnancies. However, in view of the small number of abnormal pregnancies, these observations must be considered preliminary.

Abruptio Placentae↗
PubMed1996

Effect of dehydroepiandrosterone sulfate on maternal cardiac function in term pregnancy.

To search for possible effect of dehydroepiandrosterone sulfate (DHAS) on maternal cardiac function in term pregnancy, impedance cardiographic assessments were made on 15 normal full-term pregnant women before and 5, 10, 15, 20, 25, and 30 minutes after the administration of a 200 mg intravenous dose of DHAS in 20 mL of 5% dextrose. The cardiac output, stroke volume, heart rate, and mean arterial pressure were recorded. Maternal cardiac output increased from baseline by 20% (p < 0.05) after 15 minutes and the mean increase in stroke volume was 25% (p < 0.05) after 15 minutes. No change was found in heart rate or mean arterial blood pressure. DHAS induces a significant increase in both maternal stroke volume and cardiac output without change in heart rate or mean arterial pressure, which suggests a possible increase in cardiac contractility in term pregnancy.

Blood Pressure↗