[A pilot study of low-dose TS-1 and cisplatin combination chemotherapy for advanced gastric cancer].

TS-1, a novel oral formation of 5-fluorouracil, consists of tegafur (5-FU), CDHP and Oxo. Low-dose cisplatin (CDDP) and TS-1 was evaluated in 12 patients with advanced or recurrent gastric cancer. CDDP was given biweekly at a dose of 15 mg/m2 infused for 30 minutes, and 80 mg/body of TS-1 was orally administered as many times as possible. The response rate was 41.7%. Median survival time was 13.3 months. In one case, an adverse reaction of grade 3 leucopenia was observed. Thus, thought it is necessary to watch for leucopenia, this chemotherapy could well be effective for patients with advanced or recurrent gastric cancer.

[Biweekly low-dose cisplatin and 5-fluorouracil combination chemotherapy for advanced gastrointestinal carcinoma].

Biweekly intravenous infusions of low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) were evaluated in 80 patients with advanced or recurrent gastric, colorectal, pancreatic or gallbladder adenocarcinoma. CDDP was given biweekly at a dose of 15 mg/m2 infused for 30 minutes, and 5-FU 375 mg/m2 was infused for 2 hours as many times as possible. The response rate among patients with gastric cancer was 26%, colorectal cancer 10%, pancreatic cancer 7.7%, and gallbladder cancer 42.9%. The response rates were not so high, but the median survival time of patients with recurrent gastric cancer was 17.3 months, pancreatic cancer 6.7 months, and gallbladder cancer 10.7 months. A patient with unresected advanced pancreatic head cancer with liver and para-aortic lymph node metastases received this therapy 38 times, and lived for 54 months. No severe side effects occurred in any of these cases. Thus, this chemotherapy could well be effective for the outcome of cases of advanced gastrointestinal carcinoma.

The diagnosis of internal mammary node metastases of breast cancer.

It is important to know the status of internal mammary lymph node (IMN) in estimating the prognosis in patients with breast cancer and/or planning the treatment. In the first series of this study, the diagnostic value of internal mammary lymphoscintigraphy (IMLS) and that of parasternal sonography (PS) were evaluated in 57 patients. The overall diagnostic accuracy of IMLS was 72% and that of PS, 84%, compared with IMN metastases confirmed on a biopsy. In the second series, 23 patients who underwent extended radical mastectomy and were found to have IMN metastases, were examined for the sizes and locations of metastatic IMN. Minute metastatic lymph nodes not detectable by IMLS or PS were found in 9 (39%) of the patients. However, the incidence of metastases to the first and/or second intercostal spaces was 97% for the patients. We concluded that a biopsy of the first and second intercostal spaces is useful in providing the information of IMN status.

Influence of hormones on tumor growth, cell kinetics, estrogen receptor and insulin-like growth factor-I-related protein of human breast cancer (MCF-7) cells transplanted in nude mice.

The influence of estrogens and tamoxifen on estrogen receptor (ER)-positive human breast cancer (MCF-7) cells transplanted into athymic nude mice was investigated. The mice were divided into the following three groups: (1) an E2 group with mice receiving 17 beta-estradiol dipropionate; (2) a TAM group with mice receiving tamoxifen; (3) a control group with mice given no hormone. (1) Tumor growth was significantly increased in the E2 group, but significantly decreased in the TAM group compared to control; (2) the tumor contents of insulin-like growth factor-I (IGF-I) and the rate of IGF-I-positive cells were significantly lower in the E2 group, but significantly higher in the TAM groups compared to control; (3) the IGF-I-positive cell rates were in significant inverse correlation with the [3H]thymidine-labeled cell rates in the E2, TAM and control groups. Thus, the tumor contents of IGF-I and the rate of IGF-I-positive cells were inversely correlated to the tumor growth and the [3H]thymidine-labeled cell rate in this in vivo study, although IGF-I is known to be a mitogen for breast cancer cells in vitro. Further studies are necessary to answer the questions as to the in vivo roles of immunoreactive IGF-I in ER-positive breast cancer.

Internal mammary nodal status is a more reliable prognostic factor than DNA ploidy and c-erb B-2 expression in patients with breast cancer.

We evaluated the relationship among DNA ploidy, c-erb B-2 oncoprotein expression, and clinicopathologic prognostic factors, especially axillary and internal mammary node metastases, and their value in estimating the prognosis in 128 patients with operable breast cancer. There were significant correlations between DNA ploidy and clinical stage, tumor size, or axillary or internal mammary lymph node metastases, and between c-erb B-2 expression and clinical stage or axillary lymph node metastases. In a univariate study, overall or disease-free survival was significantly correlated to clinical stage, tumor size, DNA ploidy, c-erb B-2 expression, and axillary and internal mammary node metastases. In a multivariate study, however, only axillary and internal mammary node metastases were recognized as independent factors on overall survival, whereas on disease-free survival, only axillary lymph node metastases were identified as an independent indicator. Since the DNA ploidy status and c-erb B-2 expression were closely correlated with the axillary and/or internal mammary lymph node metastases, they did not appear as independent prognostic factors in this small series.

Multivariate study of prognostic factors for differentiated thyroid carcinoma: the significance of histologic subtype.

We re-examined 239 patients with differentiated thyroid carcinoma (222 with papillary carcinoma and 17 with follicular carcinoma) especially for the clinico-pathologic entity of poorly differentiated carcinoma, and made univariate and multivariate analyses of the results to evaluate whether it would be of value in estimating the prognosis in thyroid cancer patients. In the univariate study, no significant difference was found in either survival and disease-free survival between papillary and follicular carcinomas, but between well differentiated and poorly differentiated carcinomas. In the multivariate study, however, the presence of poorly differentiated carcinoma did not appear to be an unfavorable prognostic factor. The sex, tumor size, and presence of distant metastases or grossly malignant residue in the neck after operation were, on the other hand, confirmed by the analyses to be important prognostic factors. We concluded that histologic subclassification may be less useful in estimating the prognosis in patients with differentiated thyroid carcinoma than other factors such as sex and the extent of the tumor.

Oncological aspect of immediate breast reconstruction in mastectomy patients.

In this study, we compared the relapse-free and overall survival of 83 patients who underwent mastectomy with immediate reconstruction (MIBR) using a musculocutaneous flap with or without silicone implant with those of 153 patients with breast cancer who underwent mastectomy without immediate reconstruction. In univariate analysis, the overall and/or relapse-free survival of reconstructed patients with four or more positive axillary lymph nodes or those with menopausal status were significantly inferior compared with those of nonreconstructed patients. In multivariate analysis, however, the immediate breast reconstruction did not appear to have a significant adverse influence on all patients, and on the subgroups stratified by menopausal status or axillary lymph node metastases. Therefore, it was concluded that MIBR using a musculocutaneous flap did not compromise the survival of patients with breast cancer.

C-erbB-2 oncoprotein expression versus internal mammary lymph node metastases as additional prognostic factors in patients with axillary lymph node-positive breast cancer.

The relationship was assessed between c-erbB-2 oncoprotein expression and other prognostic factors in breast cancer, such as axillary and internal mammary node metastases. The value of these indicators was analyzed in estimating prognosis, especially in patients with axillary node-positive breast cancer. These results showed that c-erbB-2 is significantly related to clinical stage and axillary node metastases. A univariate study revealed that disease-free and overall survival were correlated significantly with clinical stage, tumor size, axillary and internal mammary node metastases, and 21N status. Among the patients with axillary node involvement, however, 21N status did not appear to be a significant additional prognostic factor. Internal mammary node metastases were significant. In a multivariate study, only axillary and internal mammary node metastases were significant prognostic factors for either the entire group of patients or those with positive axillary nodes. Therefore, axillary node dissection and biopsy of the internal mammary nodes may provide important prognostic information for patients with breast cancer.

A multivariate analysis of en bloc extended radical mastectomy versus conventional radical mastectomy in operable breast cancer.

We made clinical trials of en bloc extended radical mastectomy (EXT) of a new type in 118 patients from 1980 through 1985. A variety of conventional radical mastectomies (RDL) were also performed in 105 patients from 1973 through 1985. A multivariate analysis was performed of the results to compare EXT and RDL. The result showed the 5-year survival rates of 91 +/- 2.6% and 83 +/- 3.7% were achieved for the EXT and RDL groups, respectively (Cox P value for comparison of survival curves = 0.16). Adjusted Cox regression analysis revealed a significantly favourable result of EXT (P = 0.05). This difference was most remarkable in patients with one to three metastatic axillary lymph nodes, although it was not statistically significant because of too small a number of patients available (P = 0.18). The results are thus not definite, but suggest that EXT may be advantageous over RDL especially in patients with a few metastatic axillary lymph nodes.

The relationship between lymph node metastases and DNA-ploidy status as prognostic factors in invasive breast cancer.

We evaluated the relationship between the regional lymph node metastases and the DNA ploidy status in 207 patients with invasive breast cancer, as well as their prognostic values in estimating the prognosis of breast cancer. A significantly higher incidence of aneuploidy was found in patients with a large T3 or T4 tumor, a positive axillary lymph node status, more than 4 positive axillary lymph nodes or positive internal mammary lymph nodes. In a univariate study, the overall survival was significantly correlated with tumor size, axillary lymph node status, axillary and internal mammary lymph node metastases, and DNA ploidy status. In the multivariate analysis, however, only axillary and internal mammary lymph node metastases were recognized as important independent prognostic factors on survival. In this series, the DNA ploidy status did not appear to be an independent prognostic factor either in the entire series or in negative axillary node patients, since it was closely correlated with the axillary or internal mammary lymph node metastases, and the axillary node negative patients had an extremely favorable prognosis.

Reappraisal of internal mammary node metastases as a prognostic factor in patients with breast cancer.

Clinical, histologic, and biologic prognostic factors were examined in 144 patients with invasive breast cancer. It was determined whether variable prognostic factors, especially internal mammary lymph node metastases, would serve as a basis for the prognosis of breast cancer. In a univariate study, overall survival was significantly correlated with tumor size, axillary lymph node status, axillary and internal mammary lymph node metastases, and DNA ploidy status. Especially among patients with one to three positive axillary nodes, survival in case of internal mammary involvement were significantly lower than without internal mammary involvement. In a multivariate study, only axillary and internal mammary lymph node metastases were recognized as important, independent prognostic factors of survival, but neither axillary lymph node status nor DNA ploidy status appeared as important prognostic factors. It was concluded that internal mammary lymph node metastases is additional prognostic factor, especially in patients with one to three positive axillary nodes. Because axillary and internal mammary lymph node metastases could not be predicted from their clinical assessment, axillary lymph node dissection and biopsy of internal mammary nodes may be a useful staging procedure for these patients.

A multivariate study of the relationship between regional lymph node metastases and prognosis in patients with operable breast cancer.

In order to evaluate the prognostic importance of clinical and histological node information, we made univariate and multivariate analyses of regional lymph node metastases in 223 patients with operable breast cancer who were surgically treated from 1973 to 1985. Clinical axillary node status, histological involvement of the axillary lymph nodes, their anatomical levels and numbers, and histological involvement of the internal mammary lymph nodes were selected as evaluating prognostic factors. The histological presence or absence of axillary node involvement, especially at the distal level, proved to be the most important prognostic factor. However, neither the anatomical level nor the number of histologically involved axillary lymph nodes appeared to be an important prognostic factor. On the other hand, histological involvement of the internal mammary nodes appeared to be an important and independent prognostic factor. Therefore, we concluded that axillary lymph node dissection with a biopsy of the internal mammary nodes would provide more accurate information about the prognosis of patients with operable breast cancer.

Effects of hormones on tumor growth and immunoreactive insulin-like growth factor-1 of estrogen receptor-positive human breast cancer (MCF-7) transplanted in nude mice.

The effects of estrogens and tamoxifen were analyzed on estrogen receptor-positive human breast cancer (MCF-7) transplanted into athymic nude mice. It was found that (1) the tumor growth and the proportion of 3H-thymidine-labeled cells were significantly increased in the 17 beta-estradiol dipropionate (E2) group, but significantly decreased in the tamoxifen (TAM) group with respect to the control group, and (2) the tumor content of insulin-like growth factor-1 (IGF-1) and the rate of IGF-1-positive cells were significantly lower in the E2 group, but significantly higher in the TAM group than in the control group. It was concluded that the tumor content of IGF-1 and the proportion of IGF-I-positive cells were inversely correlated to the tumor growth and the 3H-thymidine labeling index in vivo.

Lymph node metastases versus DNA ploidy as prognostic factors for invasive ductal carcinoma of the breast.

We evaluated the relationship between the DNA ploidy status and other variable prognostic factors, especially regional lymph node metastases, in 121 patients with invasive ductal carcinoma of breast, together with the value of these factors in estimating the prognostic of breast cancer. The ploidy status was diploid in 40% of the patients, and aneuploid in 60%. A significantly higher incidence of aneuploidy was found in patients with more than 4 positive axillary lymph nodes, positive internal mammary lymph nodes, or clinical stage 3 of malignancy. In a univariate study, overall survival and disease-free survival were significantly correlated with axillary and internal mammary lymph node metastases, tumor size, and clinical stage of malignancy. The disease-free survival rates for the diploid group tended to be somewhat higher than those for the aneuploid group of patients without axillary lymph node metastases. In the multivariate analysis, however, only axillary lymph node metastasis was significantly correlated with overall survival and disease-free survival. There was also a trend for the internal mammary lymph node metastases to be correlated with survival. As the DNA ploidy status was closely correlated with the axillary and internal mammary lymph node metastases, it did not appear to be an independent prognostic factor in this small series.

Immunohistochemical study of oncogene product ras p21, c-myc and growth factor EGF in breast carcinomas.

The expression of the oncogene products ras p21, c-myc and the growth factor EGF (epidermal growth factor) was studied immunohistochemically in the tissue of 119 benign and malignant human breasts. In most cases, histologically normal breast tissues and benign lesions were found to be negative or poorly-expressive for reactivity with each antibody. Similar findings were observed in carcinoma in situ. Invading breast carcinomas demonstrated a significantly higher percentage of stained cells than that observed in benign lesions or carcinoma in situ; forty-two of 66 invasive breast carcinomas (63.6%) were highly-expressive for ras p21, thirty-eight (57.6%) for c-myc and twenty (30.3%) for EGF, but overall correlations between each oncogene expression and the clinical stage, tumor size or degree of differentiation were not found. The overall 5-year survival rate was studied in 58 patients with Stage II and III in association with each oncogene or EGF expression. Their survival rate was significantly effected by the EGF expression (0.05 less than p less than 0.1) but not by ras p21 or c-myc expression. Analysis of 36 specimens available with ER (estrogen-receptor) level revealed a significant correlation between the ER status and c-myc or E2 (estradiol) and a significant inverse correlation between ER status and ras p21 or EGF expression (P less than 0.05). The expression of ras p21, EGF and c-myc was not associated with metastatic tumor progression.

Breast deformity, its correction, and assessment of breast conserving surgery.

A combination of quadrantectomy, axillary dissection, and radiotherapy (QUART) is the regimen most favored by Japanese surgeons among a variety of breast conserving therapies currently available against breast cancer. Unfortunately, extensive resections such as quadrantectomy often give poor local cosmetic results in patients with small breasts. With the aim of improving the cosmetic aspect after an extensive resection, immediate transposition of the latissimus dorsi muscle (LDM) was carried out in breast conserving surgery. To date, twenty-one patients have been entered in this study. Post-quadrantectomy breast deformity was not corrected in six patients including one with bilateral breast cancers, but was corrected by transposition of a part of LDM in 14 other patients. In the last patient, who also had bilateral breast cancers, the right breast was treated by QUART and the left breast by subcutaneous mastectomy followed by transposition of LDM. The cosmetic outcome for these patients was assessed both subjectively and objectively; the objective assessment used a Moire topography camera. The postoperative appearance and topography revealed a satisfactory symmetry of breasts in the transposed patients, especially those with small breasts, when compared with non-transposed patients. It may be concluded that the transposition of LDM is useful in preventing breast deformity following an extensive resection in breast conserving surgery.

Effects of the prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in Sprague-Dawley rats fed a high- or low-fat diet.

The effects of indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor content of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma have been examined in female Sprague-Dawley rats. The rats were fed either a high-fat (20% corn oil) or low-fat (0.5% corn oil) diet with or without 0.005% indomethacin starting 7 days after intragastric administration of a single dose of 5 mg 7,12-dimethylbenz(a)anthracene. The results demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as demonstrated by a decreased tumor incidence, a decreased number of tumors per group, and an increased latency. Contrary to what had been expected, however, indomethacin promoted tumor proliferation in both the high- and low-fat diet groups, as evidenced by an increased tumor size, an increased bromodeoxyuridine-labeling index, and a decreased potential tumor-doubling time. No significant difference in either the estrogen receptor or progesterone receptor content of the tumor was noted. It can be concluded, therefore, that indomethacin significantly reduced tumorigenesis in the high-fat diet group but significantly promoted tumor proliferation in both the high- and low-fat diet groups.

Effects of tamoxifen, medroxyprogesterone acetate and estradiol on tumor growth and oncogene expression in MCF-7 breast cancer cell line transplanted into nude mice.

The effects of three hormonal agents with a different mechanism of action (tamoxifen [TAM], medroxyprogesterone acetate [MPA] and estradiol [E2]) on tumor growth, differentiation and oncogene expression were evaluated using the estrogen-receptor positive human breast carcinoma cell line MCF-7 transplanted into nude mice. In MCF-7 tumors treated with E2, tumor incidence, mean weight of tumors, 3H-thymidine labelling index, differentiation antigen HMFGM (human milk-fat globule membrane) and ras p21, c-myc, neu oncogene products, the level was significantly increased. On the other hand MPA suppressed all of them. TAM increased the level of c-myc expression and HMFGM antigen, but suppressed the others. This evidence indicates that E2 induces both proliferation and differentiation of MCF-7 tumor cells. MPA suppresses both proliferation and differentiation, and TAM induces differentiation and suppresses proliferation.

[Effect of high dietary fat on the total DNA and receptor contents in rats with 7,12-dimethylbenz[A]anthracene-induced mammary carcinoma].

The influences of high dietary fat on the malignant intensity and the hormone receptors of DMBA-induced mammary breast carcinoma were analyzed in female Sprague-Dawley rats. The rats were fed either a low-fat diet or high-fat diet after the DMBA administration. As the results, incidence, size, average latent period, DNA histogram, DNA index and % of S-phase fraction of tumor were significantly different between both groups. But the ER and PgR contents were not different between both groups. The results suggest that a high dietary fat could increase the malignant intensity of the tumor but does not influence the receptor contents of the tumors.

Immunohistochemical demonstration of growth factors, TGF-alpha, TGF-beta, IGF-I and neu oncogene product in benign and malignant human breast tissues.

The expression of growth factors, TGF-alpha, TGF-beta, IGF-I and neu oncogene product was studied immunohistochemically in the tissue of 120 benign and malignant human breasts. Growth factors were found only in benign or malignant mammary epithelial cells and not in stromal cells. Normal and benign lesions were found to be negative for reactivity with each antibody. Carcinoma in situ and invasive breast carcinomas demonstrated a significantly higher percentage of stained cells than that observed in benign lesions; forty (49%) of 82 invasive carcinomas were positive for TGF-alpha, 31 (38%) for TGF-beta, 31 (38%) for IGF-I and 34 (41%) for neu product. No overall correlations were found between expression of each growth factor and the clinical stage or degree of histologic differentiation of the carcinomas. A significant positive correlation was observed between ER status and IGF-I expression and between PgR status and TGF-beta expression. In the majority of the carcinomas, co-expression between TGF-alpha, TGF-beta and IGF-I was observed; the percentage of cases with parallel positive or negative expression of two growth factors was as follows; TGF-alpha - TGF-beta (70%), TGF-alpha - IGF-I (57%), TGF-beta - IGF-I (71%). The concomitant expression of TGF-alpha and neu oncogene product in cell surface was also observed. The relapse-free intervals of the patients were studied in association with expression of each growth factor. TGF-beta-positive tumors showed a significantly better prognosis than TGF-beta - negative tumors (within the first 2 years of observation). However, TGF-alpha, IGF-I and neu overexpression showed no effect on the prognosis of the patients.