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.

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.

Bilateral cervical lymph node metastases in well-differentiated thyroid cancer.

We analyzed the regional lymph node metastases of 98 patients with thyroid cancer who underwent bilateral modified neck dissection. Bilateral jugular lymph node metastases were frequent in patients with papillary carcinoma of the thyroid, especially in those patients with obvious carcinoma in both lobes of the gland, cancer arising in the isthmus, clinically detectable bilateral lymphadenopathy, and recurrent thyroid cancer. In patients whose cancer was clinically confined to one lobe, and where there were no obviously enlarged contralateral lymph nodes, the occurrence of contralateral jugular lymph node metastasis was significantly correlated with the contralateral paratracheal lymph node metastasis. The bilateral lymphadenectomy appears to be appropriate in these instances.

Wide resection with latissimus dorsi muscle transposition in breast conserving surgery.

In this study we evaluated whether the immediate transposition of the latissimus dorsi muscle (LDM) improves breast appearance and patient satisfaction after quadrantectomy. Twenty-three patients (transposed group) had the transposition of LDM immediately after quadrantectomy, but eight patients (non-transposed group) had quadrantectomy alone. For evaluation, breast size was classified as small (A or B cup) and large (C or D cup). Consequently, the cosmetic result was evaluated as excellent in 73% of the patients with transposed small breasts, but in only 25% of the patients with non-transposed small breasts and by none of the patients with transposed large breasts. On the other hand, all patients with transposed small breasts reported that they are satisfied with their operation, as opposed to 88% of the patients with transposed large breasts and 63% of the patients with transposed large breasts and 63% of the patients with non-transposed small breasts. It was concluded therefore, that the transposition of LDM is useful in correcting post-quadrantectomy breast deformity, especially in patients with small breasts.

The expression of E-cadherin as a prognostic factor in breast cancer.

We examined the clinical significance of E-cadherin expression in 98 patients with breast cancer. E-cadherin expression significantly correlated with histologic grade (p=0.0323) and tended to correlate with the absence of axillary lymph node metastases (p=0.0646). The expression of E-cadherin was associated significantly with the recurrence rate (p=0.0334) and marginally associated with disease-free (p=0.0597) but not overall survival, in univariate analysis. The association between E-cadherin expression and disease-free survival was lost in multivariate analysis. The prognostic value of E-cadherin expression in breast cancer appears to be limited. A larger, prospective study with long-term follow-up is needed.

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.

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.

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.

Mastectomy with and without immediate breast reconstruction using a musculocutaneous flap.

We compared surgical cosmetic results in 83 patients who underwent mastectomy with immediate breast reconstruction (MIBR) using a myocutaneous flap with those of 153 patients with breast cancer who underwent mastectomy without breast reconstruction. Cosmetic results were significantly better in patients who underwent MIBR than radical mastectomy or extended MIBR, although no intergroup difference existed in the reconstructive technique. Neither did any difference exist in the incidence of complications between patients undergoing MIBR and mastectomy without breast reconstruction, or between patients undergoing modified mastectomy and radical or extended mastectomy. Finally, MIBR did not appear to adversely effect recurrence or overall survival. We conclude that MIBR using a myocutaneous flap is an acceptable treatment option for patients with breast cancer.

Adjuvant chemotherapy with a combination of mitoxantrone, methotrexate, 5-fluorouracil for node-positive breast cancer: phase II pilot study.

A phase II pilot study was carried out on 30 patients to ascertain the toxicity and efficacy of combination chemotherapy with mitoxantrone, methotrexate, 5-fluorouracil (NMF) in the adjuvant setting for axillary lymph node-positive breast cancer. The NMF regimen was mitoxantrone 10 mg/m2, methotrexate 40 mg/m2, and 5-fluorouracil 600 mg/m2 administered i.v. on day 1, repeated every 3-4 weeks for 6 cycles. The median nadir WBC count was 2,000/microl; grade 4 leukocytopenia occurred only in 1 patient. Nausea and vomiting appeared as grade 0 and 1 severity in 26/30 patients. Alopecia was extremely mild, appeared as grade 0 and 1 in 29/30 patients. The overall and relapse-free survival rates were 67.8% and 68.4% at the 82-month follow-up, respectively. The overall survival rate in premenopausal patients was significantly better than that in postmenopausal patients (P<0.05). NMF is a well-tolerated combination regimen, suitable as adjuvant chemotherapy for node-positive breast cancer.

Biology and surgical management of breast cancer.

The surgical treatment of breast cancer has been a source of controversy. The controversy arises from the differences in physicians' philosophies regarding the biology of breast carcinoma. Traditionally, surgeons have emphasized the potential therapeutic value of regional lymph node dissection, maintaining that adequate loco-regional treatment is of prime concern in patients with localized tumors. On the other hand, medical oncologists have always stressed the systemic nature of cancer. However, breast cancer is a very heterogeneous disease with an enormous range of different biologic characteristics, and new information is continually becoming available on the natural history of breast cancer. Therefore, we should seek a more rational theory based on the clinical evidence which can explain the biologic characteristics of breast cancer. We have proposed a new spectrum hypothesis as follows: (a)tumor cells traverse lymphatics to lymph nodes by direct extension, and there is an orderly pattern in the early stage of lymph node metastases; (b)regional lymph nodes are able to trap tumor cells but are ineffective or incomplete barriers to tumor cell spread; (c)regional lymph nodes have biologic importance, and a positive lymph node is an indicator of a host-tumor relationship that correlates with the subsequent appearance of distant disease; (d)lymphatic and hematogenous dissemination occur not serially, but in a parallel fashion; (e)many palpable invasive breast cancers are a systemic disease, but non-invasive or minimally invasive breast cancers are likely to be a local disease; (f)early detection and treatment of in-breast cancer improves survival, but variations in regional therapy are unlikely to have a major influence on survival.

Sentinel lymph node biopsy in breast cancer using blue dye with or without isotope localization.

BACKGROUND: The purpose of this study was to determine the feasibility of sentinel lymph node (SLN) biopsy using blue dye with or without isotope localization to predict the presence of axillary and internal mammary lymph node (IMN) metastases in patients with breast cancer. We also investigated whether multiple sectioning of the SLN could improve the accuracy of frozen section examination. METHOD: One-hundred twenty-six patients underwent dye-guided or dye- and gamma probe-guided SLN biopsy followed by complete axillary lymph node dissection (ALND). No ALND was performed in the 14 patients with small tumors and a negative SLN. In addition, 69 patients underwent IMN biopsy. RESULTS: The axillary SLN was identified in 123 of 140 (88%) patients. An accuracy rate of 90% was obtained by frozen section examination of the SLN, which increased to 100% in patients examined with a greater number of sections. Lymphatic flow to the IMN and/or a radioactive hot spot in the IMN was found in 9 of 102 (9%) patients, while a hot node was detected using a gamma probe in only 2 of these patients. No involvement of the IMNs was found histologically in these 9 patients. IMN involvement was found in 7 of 61 (11%) patients without lymphatic flow to the IMNs or a hot spot by lymphoscintigraphy or who did not undergo lymphoscintigraphy. CONCLUSION: ALND can be avoided in patients with small breast cancers and a negative SLN. SLN biopsy guided by lymphatic mapping is unreliable for identifying metastases to IMNs.

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.

Immediate transposition of a latissimus dorsi muscle for correcting a postquadrantectomy breast deformity in Japanese patients.

With the aim of improving cosmetics after quadrantectomy, an immediate transposition of latissimus dorsi muscle was carried out. Cosmetic breast changes in transposed and non-transposed patients were evaluated by a Moire topography camera. To date, the breast deformity in five patients has been corrected only by conization of the residual breast tissue, and the breast deformity in the other five patients has been corrected by transposed latissimus dorsi muscle. Postoperative appearance and topography showed satisfactory symmetry of breasts in the transposed patients, when compared with the non-transposed patients. We conclude that the immediate transposition of latissimus dorsi muscle is useful for preventing post-quadrantectomy breast deformity.

Breast cancer and regional lymph node dissections.

Regional lymph node metastases were evaluated in 289 patients with operable breast cancer. The metastases of the axillary and internal mammary lymph node were shown to be closely related to the survival of patients, but the status of these nodes was shown to be impossible to estimate before the operation. Thus, axillary and internal mammary node dissections seem to be very important in order to attain an acceptable amount of information for staging of certain breast cancer patients. Due to the radicality of operations including internal mammary node dissection, the use of modified extended mastectomy is proposed as the staging operation. In this manner, the anterior chest deformity created by an extended radical mastectomy can be avoided and the pectoralis major muscle spared in patients without internal mammary lymph node involvement. Also found in this study, was some evidence of the beneficial use of en bloc extended radical mastectomy for the survival of a selected group of patients.

Effects of high and low dietary fat and indomethacin on tumour growth, hormone receptor status and growth factor expression in DMBA-induced rat breast cancer.

The effects of high and low dietary fat (20% vs. 0.5% corn oil), and of the prostaglandin synthetase inhibitor indomethacin (0.005% w/w), on tumour incidence, tumour growth, hormone-receptor status and growth-factor expression were examined in dimethylbenzanthracene (DMBA)-induced rat breast cancer. The high dietary-fat group showed a significantly higher tumour incidence, larger tumour size and larger number of bromodeoxyuridine(BrdU)-positive cells of tumours as compared with those in the low dietary-fat group. Indomethacin reduced tumour incidence significantly, but conversely increased the tumour size and the number of BrdU-positive cells in both the high and the low dietary-fat groups. No significant difference was noted in the hormone-receptor status of the tumours. Growth factors (TGF-alpha and IGF-II) were somewhat highly expressed in the high dietary-fat group as compared with the low dietary-fat group, but indomethacin rather reduced the growth-factor expression. It is concluded that high dietary fat stimulates tumour incidence and tumour proliferation, while indomethacin has dual effects: a stimulating effect on tumour proliferation, but an inhibiting effect on tumour incidence. It is also suggested that hormone-receptor status and growth-factor expression do not play an important role in their stimulating effects on tumour proliferation.

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.

Impact of neck dissection on survival in well-differentiated thyroid cancer: a multivariate analysis of 218 cases.

The management of cervical lymph node metastases in well-differentiated carcinoma of the thyroid has been highly controversial. In the Department of Surgery (II), Kanazawa University Hospital, the surgical management of cervical lymph node metastases in curable well-differentiated carcinoma of the thyroid has been changed from a conservative approach to an aggressive one since 1973. In order to determine whether an aggressive approach for cervical lymph node metastases is adequate, a retrospective multivariate analysis was carried out of 218 cases of well-differentiated thyroid cancer. The patients have been followed up from 5 to 30 years. Multivariate analysis was conducted following Cox's model. As for the results, the aggressive management of cervical lymph node metastases appeared to have an impact on survival. Furthermore, age and sex were confirmed to be important prognostic factors and a partial lobectomy was confirmed to be inadequate as a type of thyroidectomy.

Breast conserving treatment versus modified radical mastectomy in Japanese patients with operable breast cancer.

From January, 1988 to October, 1995, 96 patients with operable breast cancer were treated by breast conserving treatment (BCT) including wide excision and axillary dissection followed by breast radiation. During the same period, 188 patients were treated by modified radical mastectomy (MRM) with or without breast reconstruction. In order to compare the survival of BCT and MRM groups, univariate and multivariate analyses were performed in this retrospective study. Univariate analysis revealed that the 5-year survival rates in the BCT and MRM groups were 97% +/- 2% and 87% +/- 3%, respectively (p < 0.05 with the Cox-Mantel test). However, the baseline variables were different between the groups. The adjusted Cox regression analysis revealed that the results of BCT were almost equivalent with those of MRM. Moreover, no breast recurrence was found in the BCT group. Therefore, it is suggested that our technique of BCT is as effective as modified radical mastectomy in treating operable breast cancer in Japanese patients.

[Sentinel lymph node biopsy and axillary lymph node dissection].

Sentinel lymph node (SLN) biopsy is a useful way of assessing axillary status and obviating axillary dissection in patients with node-negative breast cancer. A combination of dye- and gamma probe-guided methods can identify SLN more accurately and easily than either of these techniques alone. On the other hand, SLN biopsy is highly accurate and sensitive in patients with small tumors, and no false-negative SLN biopsy has been reported for a breast cancer < 1.0-1.5 cm. Moreover, extensive intraoperative examination of SLNs using frozen sections can attain a sensitivity comparable to that obtained by histologic examination on the permanent sections. In practice, therefore, axillary dissection can be avoided in patients with small tumors in whom the SLNs are negative.