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Biomedical subjects

M Toi

Publications and source records attributed to M Toi.

At least 109 records · Page 6Linked to original sources
PubMed1998

Prognostic Factors for Node-negative Breast Cancers: Results of a Study Program by the Japanese Breast Cancer Society.

BACKGROUND: Prognostic factors for predicting the recurrence of node-negativebreast cancers have been controversial. The present study was performed to elucidate practically useful prognostic factors using formalin-fixed paraffin sections. METHODS: This was a case-controlled multi-institutional study that composed 40 patients with recurrent node-negative breast cancer and 80 patients with node-negative breast cancer but without recurrence after radical surgery. Tumors weresmaller than 3 cm in diameter and were treated surgically between January 1, 1985 and December 31, 1990. The recurrent and non-recurrent cases were matched with regard to their age, adjuvant chemotherapy and the year in which surgery was performed. Fourteen immunohistochemical factors and 8 histological factors of theprimary tumor were studied on formalin-fixed, paraffin-embedded sections by immunohistochemical and histochemical analyses. RESULTS: According to univariate analysis, factors such as progesterone receptor (PgR), MIB-1, CD44v6, CD44v9 and platelet-derived endothelial cell growth factor (PDECGF) were significantly different between the recurrent and non-recurrent groups (p &ly; 0.1; Wilcoxon-Mann-Whitney analysis). Chi-squared test showed significant differences in MIB-1, cdc2 and stromal plasminogen activator receptor (suPAR). Histologically, mitotic count was also significantly different between the two groups (p < 0.005). Multivariate analysis revealed that positivity for cdc2 (p=0.01), high mitotic count (p=0.04) and negativity for CD44v9 (p=0.02)were independent prognostic factors among variables selected by univariate analysis, and that positivity for MIB-1 (p=0.03) and cdc2 (p =0.01), and negativity for CD44v9 (p =0.03) were independent prognostic factors among the immunohistochemical markers examined. CONCLUSION: Our results indicated that positivity for MIB-1 and cdc2, high mitotic count and negativity for CD44v9 could serve as independent factors for predicting the recurrence of node-negative breast cancer.

Journal Article↗
PubMed1998

Metalloproteinases and tissue inhibitors of metalloproteinases.

Because the proteolytic degradation of extracellular matrix is required for invasion and metastasis, it would appear that the important family of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) might be prognostic indicators of the invasive potential of a breast tumor. Nevertheless, there are few data demonstrating an independent prognostic value of any individual MMPs or TIMPs in primary breast cancer patients. It is possible, however, that the balance among levels of certain MMPs and their inhibitors will be more informative, since MMPs are clearly involved in paracrine tumor-stromal interactions and are associated with angiogenesis, which does appear to be prognostic.

Breast Neoplasms↗
PubMed1998

Role of MDM2 overexpression in doxorubicin resistance of breast carcinoma.

Several oncoproteins or tumor suppressor gene products have been indicated to be of value as predictors of the de novo resistance to cytotoxic agents. In this study, we have investigated the role of MDM2 (murine double minutes) overexpression in doxorubicin resistance of breast cancer. Immunocytochemical analysis demonstrated that MDM2-positive tumors, even with p53-negative phenotype, were significantly more resistant to doxorubicin treatment compared to MDM2-negative tumors. An in vitro experimental model using stable mdm2-transfected MCF-7 cells carrying wild-type p53 confirmed that the cells become approximately 3-fold more resistant to doxorubicin as a result of MDM2 overexpression, and the wild-type p53 function, such as the induction of p21Waf1 following DNA damage, was significantly suppressed. MDM2 overexpression is suggested to be a novel marker for predicting lack of response to doxorubicin treatment in breast cancer patients.

Antibiotics, Antineoplastic↗
PubMed1998

Prognostic significance of p53, angiogenesis, and other conventional features in operable breast cancer: subanalysis in node-positive and node-negative patients.

To validate the prognostic value of the determination of p53 expression, intratumoral microvessel density (IMD) (a measure of angiogenesis), and the conventional features, we studied 531 patients operated of breast cancer (271 node-positive and 260 node-negative), with a median follow-up exceeding 6 years. IMD was assessed by using the anti-CD31 antibody to identify the microvessels. p53, estrogen receptor (ER) and progesterone receptor (PgR) were determined by immunocytochemistry using the antibodies PAb1801, H-222 Sp2y and KD-68, respectively. The prognostic value of the markers was analyzed by univariate and multivariate statistical analyses. In the overall series p53 expression, IMD, nodal status, ER and PgR were statistically significant prognostic indicators for both relapse-free survival (RFS) and overall survival (OS) in the final multivariate model. Likewise, tumor size and menopausal status were significant prognostic indicators for RFS and OS, respectively. In the subgroup of node-negative patients who did not receive adjuvant therapy only p53, IMD, and tumor size were statistically significant in multivariate analysis. In the subgroup of node-positive patients treated with adjuvant chemotherapy, IMD, the number of involved nodes and PgR were statistically significant in multivariate analysis. In the subgroup of node-positive patients treated with adjuvant tamoxifen, IMD and ER (and the number of involved nodes, only for OS) were statistically significant for both RFS and OS in the final multivariate model. Different markers played a diverse prognostic role in the diverse subgroups studied. Angiogenesis was the sole marker which retained prognostic value in all the sub-groups analyzed. p53 retained significance only in the subgroup of node-negative patients, whilst ER and PgR were statistically significant in the subgroups of node-positive patients treated with adjuvant hormone therapy or chemotherapy, respectively.

Adult↗
PubMed1998

Significance of circulating hepatocyte growth factor level as a prognostic indicator in primary breast cancer.

The circulating hepatocyte growth factor (HGF)/scatter factor level is frequently increased in advanced cancer patients. In this study, we have assessed the prognostic value of the circulating HGF level determined by enzymatic immunoassay in primary breast cancer patients. Of 200 primary breast cancer patients, 54 (27.0%) showed the increase of serum HGF level according to the age-matched cutoff values. The prognosis of the patients with the increased HGF level was statistically worse than that of the patients with normal HGF level (P = 0.0001, log-rank test). Multivariate analysis confirmed that the increase in HGF level was an independent prognostic indicator in primary breast cancer patients. In the background analysis, the increase in serum HGF level was significantly associated with tumor size, nodal status, and histological evidence of venous invasion. The data indicate that up-regulation of the circulating HGF level may predict systemic tumor spread and early relapse in primary breast cancer patients.

Adult↗
PubMed1998

[Antiangiogenic therapy].

Tumor vasculature is a promising novel target for anticancer treatment. Natural or synthetic products have been developed, and endogenous inhibitors such as angiostatin have been extensively analyzed. Several inhibitors are currently under investigation, and many compounds are tested in pre-clinical trials. This review provides an overview of the antiangiogenic treatments as well as early clinical result with these agents.

Angiostatins↗
PubMed1997

MDM2 in Breast Cancer.

The MDM2 protein, an oncogene product, is known to act by suppressing p53 function. Although gene amplification of MDM2 was frequently detected in human sarcomas, it was uncommon in the majority of epithelial tumors including breast cancer. However, recent reports have demonstrated that its translational activity is enhanced in a variety of carcinomas. In this report, we summarized the implications of MDM2 overexpression in human breast cancer from the literature as well as our preliminary results.

Journal Article↗
PubMed1997

Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma.

BACKGROUND: The clinical outcome is generally positive for patients with node-negative breast carcinoma (i.e., those who do not have detectable metastases in the lymph nodes) who have been treated with surgery or surgery plus radiation therapy. In about 30% of the patients, however, the disease recurs, and they are at risk of death. Determination of valid new prognostic indicators would improve the ability to identify patients at high risk of recurrence. Breast cancer can entail substantial development of new blood vessels within the tumor tissue, and it is known that the growth and metastasis of solid tumors are dependent on such angiogenesis. The conversion of tumor cells to an angiogenic phenotype may be preceded by a change in the balance of angiogenic growth factors and angiogenesis inhibitors. PURPOSE: This study was conducted to determine if the levels of vascular endothelial growth factor (VEGF) protein, a potent endothelial growth factor and mediator of vascular permeability and angiogenesis, measured in the primary tumors of women with node-negative breast cancer are associated with known prognostic factors and patient survival. METHODS: By use of a selective enzymatic immunoassay, levels of VEGF protein were measured in cytosolic extracts of primary tumor tissue surgically obtained from 260 women with node-negative breast carcinoma who had been treated with surgery with or without radiation therapy but not with adjuvant therapy and who had been followed for a median time of 66 months. The relationships between VEGF concentrations and other prognostic dichotomous variables or clinical outcome were tested by the use of the Kolmogorov-Smirnov test and univariate and multivariate Cox analyses, respectively. The relationship between VEGF and hormone receptors (i.e., those for estrogen and progesterone) was examined by the use of Spearman's correlation analyses. All P values resulted from the use of two-sided statistical tests. RESULTS: Tumors from 247 (95%) of the 260 patients had detectable VEGF, ranging in concentration from 5.0 to 6523 pg/mg protein (median, 126.25 pg/mg protein). No statistically significant associations were found between VEGF and the other prognostic factors (e.g., age, menopausal status, histologic tumor type, tumor size, and hormone receptors) examined. Levels of VEGF were found to be prognostic for both relapse-free and overall survival in univariate and multivariate analyses (likelihood ratio tests; all four P values < .001). In the multivariate analysis, the first-order interaction term of VEGF and estrogen receptor was also prognostic for overall survival (likelihood ratio test; P = .05). CONCLUSIONS: The results show that cytosolic levels of VEGF in tumor tissue samples are indicative of prognosis for patients with node-negative breast carcinoma.

Adult↗
PubMed1997

Outcome of surgical resection for chest wall recurrence in breast cancer patients.

BACKGROUND: Although recurrent breast cancer is a systemic disease, there might be several exceptions where local treatment has a favorable outcome. METHODS: From 1989 to 1996, 15 patients underwent full thickness chest wall resection, supported by peri- and postoperative systemic treatments for patients with isolated chest wall recurrences, including soft tissue local recurrence and parasternal lymph node metastasis. RESULTS: The 5-year survival rate after surgical removal was 47%. Patients with > 5-year disease-free intervals (DFI) after mastectomy showed a long survival after chest wall resection. Local failures appeared in four cases whose surgical margins were positive. No serious complication except one pyothorax occurred after surgery. CONCLUSIONS: It is suggested that surgical treatment with a full thickness chest wall resection might have a favorable prognosis for selected patients with solitary lesion and long DFI.

Adult↗
PubMed1997

Co-determination of the angiogenic factors thymidine phosphorylase and vascular endothelial growth factor in node-negative breast cancer: prognostic implications.

Experimental and clinical studies have shown that human breast cancer is an angiogenesis-dependent neoplasm. In fact, several authors have demonstrated that the determination in primary tumors of the degree of vascularization (microvessel counts) as well as of some angiogenic peptides is of prognostic value. However, which are the most important mediators of angiogenesis and their relationship with other relevant biological markers needs further investigation. In the series of 260 women with node-negative breast cancer (NNBC) on which we previously assessed vascular endothelial growth factor (VEGF), we have now also determined thymidine phosphorylase (TP) protein as well as p53 protein and Cathepsin-D cytosolic levels using immunometric methods. The median concentrations of TP, p53 and Cathepsin-D were 105.4U/mg (range 1.2-843.1), 0.22 ng/mg (range 0.0-41.65) and 33.80nmol/mg (range 4.20-216.0), respectively. We found that TP concentrations were associated with Cathepsin-D and p53, but not with VEGF. VEGF (p<0.0001) and p53 (p = 0.03 and p = 0.012, respectively) were found to be statistically significant prognostic variables for both relapse-free survival (RFS) and overall survival in univariate analysis. Conversely, TP and Cathepsin-D levels did not correlate with prognosis. In multivariate analysis for RFS, VEGF levels (p<0.0001), TP levels (p = 0.050) and their first-order interaction terms (p = 0.027) were statistically significant prognostic indicators. Cathepsin-D and p53 protein levels did not retain significance in the model inclusive of all the above variables. The predictive capability of the complete model was satisfactory (Harrell c statistic = 0.72). Moreover, these results suggest a possible potentiation of the capability of predicting the likelihood of recurrence by the co-determination of TP and VEGF. The probability of recurrence was particularly high in the patients with primary tumors characterized by elevated levels of both angiogenic factors. This is the first study showing in vivo that two different angiogenic peptides concur in the progression of human breast cancer. The biology and possible therapeutic implications of this observation are discussed.

Journal Article↗
PubMed1997

Increase in the circulating level of hepatocyte growth factor in gastric cancer patients.

We measured serum concentrations of hapatocyte growth factor (HGF) in patients with gastric cancer and compared these with the histological findings and conventional tumour markers, including CEA, CA19-9 and CA125, for evaluation of the significance of serum HGF levels as a tumour marker. The HGF levels were measured by an enzyme-linked immunosorbent assay (ELISA) system. The average levels of serum HGF in 89 healthy control subjects, 104 patients with primary gastric cancer and 15 patients with recurrent gastric cancer were 0.31 +/- 0.11 ng ml(1), 0.42 +/- 0.50 ng ml(-1) and 0.92 +/- 0.39 ng ml(-1) respectively. The average level in patients with recurrent disease was significantly higher than in healthy control subjects and in primary cancer patients (P< 0.001 and P< 0.003 respectively). Of 104 patients with primary gastric cancer, 35 (33.7%) showed an aberrant increase in the circulating level of HGF. The increased HGF levels were significantly associated with the degrees of histological tumour invasion and venous invasion. Of 15 patients with recurrent gastric cancer, 14 (93.3%) showed an aberrant increase. No correlation was found between serum HGF levels and CEA levels, CA19-9 levels and CA125 levels. However, the rate of the aberrant increase in HGF levels was significantly higher than that of any other tumour markers, including CEA, CA19-9 and CA125, in primary gastric cancer patients. In conclusion, the circulating levels of HGF were elevated in approximately one-third of patients with primary gastric cancer, particularly in those with high grades of histological tumour invasion and venous invasion, and frequently in patients with distant metastases, suggesting that HGF might play important roles in the tumour progression of gastric cancer. Furthermore, serum HGF levels may be of value as a tumour marker in patients with gastric cancer.

Adult↗
PubMed1997

[Determination of intratumoral estrone (E1) and estradiol (E2) in primary breast cancer tissues by sensitive HPLC-RIA].

The alternation of intratumoral estrogen metabolism has been indicated in breast cancer tissues. We determined the intratumoral concentrations of estrone (E1) and estradiol (E2) by a sensitive HPLC-radioimmunoassay (RIA) and analyzed its clinical significance in 74 primary breast cancer tissues. The average intratumoral concentrations of E1 were 48.6 + 7.3 pg/g w.w and 80.6 + 43.2 pg/g w.w in pre- and post-menopausal patients, respectively. The E2 concentrations were 168.7 + 36.8 pg/g w.w and 104.7 + 23.6 pg/g in pre- and post-menopausal patients, respectively. The background analysis demonstrated that intratumoral E2 levels were significantly higher in estrogen receptor (ER) positive tumors compared to ER negative tumors (p < 0.01). A significant correlation was also found between intratumoral E2 concentrations and progesterone receptor (PgR) status, indicating that E2 synthesis is frequently upregulated in hormone dependent tumors. These findings are important for studying the hormonal microcircumstances of Japanese breast cancer patients and also for considering the indication for clinical treatment using aromatase inhibitors.

Adult↗
PubMed1997

[The feasibility of CEF (cyclophosphamide, epirubicin, 5-FU) regimen in the adjuvant setting of primary breast cancer].

In Japan, 5-FU/5-FU derivatives or the combination therapy of CAF (cyclophosphamide, CPA; adriamycin, ADM; 5-fluorouracil; 5-FU) have been commonly used for the adjuvant treatment of breast cancer. Recently, a combination of CEF (CPA; Epirubicin, EPI; 5-FU) has come to the stage of adjuvant setting, because the cardiotoxicity was reduced in EPI. In this study, we investigated the feasibility of 6 cycles of CEF (CPA 700 mg/m2, EPI 70 mg/m2, 5-FU 700 mg/m2; day 1 iv every 3-4 weeks) in the adjuvant treatment of primary breast cancer patients with nodal involvements. All 12 patients completed 6 cycles of CEF within 8 months. The median treatment duration was 6.2 months. More than Grade III side effects of neutropenia, nausea/vomiting and alopecia were observed in 7/12 (58.3%), 5/12 (41.7%) and 12/12 (100%), respectively. No serious side effects, including cardiotoxicity, were shown. CEF seems to be feasible regimen as an adjuvant treatment for breast cancer.

Adult↗
PubMed1997

[New molecular target of cancer therapy--angiogenesis regulator VEGF].

Recent studies on angiogenesis in human solid tumors have underlined its importance as therapeutic target. In particular, of interest is to suppress the function of several positive regulators including vascular endothelial growth factors (VEGF), basic fibroblast growth factor and thymidine phosphorylase, because they are evident to be responsible for the promotion of neovascularization in a variety of tumor types. In this review, we picked up VEGF, probably one of most promising target, and discuss about the therapeutic tools for controlling VEGF function in human tumors.

Antibiotics, Antineoplastic↗
PubMed1996

Quantitative analysis of vascular endothelial growth factor in primary breast cancer.

BACKGROUND: Recent clinical studies have demonstrated that tumor angiogenesis is a potent prognostic indicator for breast cancer patients. The quantitation of endothelial growth factors is thought to be useful to assess angiogenic phenotype in the tumor. Among the many new endothelial growth factors, vascular endothelial growth factor (VEGF) is known to be particularly responsible for promoting the neovascularization in human breast cancer. METHODS: Intratumoral protein levels of VEGF were measured by enzymatic immunoassay in 135 primary breast cancer tissues. The VEGF levels were compared with the microvessel density evaluated by immunostaining the endothelial antigen and also were compared with intratumoral protein levels of other endothelial growth factors, including basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF). RESULTS: Intratumoral VEGF concentrations varied from 3.3 pg/mg protein to 2032 pg/mg protein (average 148 pg/mg protein). An immunocytochemical analysis using anti-VEGF antibody confirmed that VEGF was located mainly in the cytoplasm of the tumor cells. The VEGF concentrations were significantly higher in vascularly rich tumors than in vascularly poor tumors. No significant association was found between VEGF concentrations and the two other endothelial growth factor concentrations. CONCLUSIONS: The quantitation of intratumoral VFGF levels seems to be useful for assessing the activity of tumor angiogenesis.

Breast Neoplasms↗
PubMed1996

Protective effect of leuprolide acetate on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats.

The anti-carcinogenic effect of TAP-144-SR biodegradable microcapsules of copoly (DL-lactic/glycolic acid) copolymer containing a potent LHRH agonist, TAP-144 (D-Leu6-(des-Gly10-NH2)-LHRH ethylamide, leuprolide acetate) was investigated in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumours. At 50 days of age, all rats were given 20 mg doses of DMBA by gastric intubation. Rats on the Initiation Group were given a single s.c. injection of TAP-144-SR (3 mg/kg) 1 week before DMBA treatment, and rats in the Promotion Group were given repeated s.c. injections every fourth week from 1 week after DMBA treatment until the end of the experiment. In the Initiation Group, tumour incidence and multiplicity were reduced to 20.8% and 15.0% of the Control Group values, respectively. In the Promotion Group, tumour incidence and multiplicity were also reduced to 17.7% and 7.9%, respectively. It was suggested that TAP-144-SR may be a potential candidate as an agent for hormonal chemoprevention in breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗