A study on telomerase activity and prognosis in breast cancer.

There are still many questions to be elucidated concerning the relationship between telomerase activity and various factors associated with cancer. Whether or not the level of telomerase activity could be a prognostic factor in breast cancer was investigated through 5-yr follow-up observation. Telomerase activity was quantified by the fluorescence-based telomeric repeat amplification protocol assay in 54 patients with breast cancer and its relationship with patient prognosis was examined. Telomerase activity was detected in 92.6% of breast cancer patients, with a median of 65.4 TPG (total product generated) (Min 0-Max 446.2). The follow-up observation for 5 yr demonstrated that among background factors examined, recurrence was the only factor that showed a significant association with the level of telomerase activity when a cutoff at 100 TPG was adopted. This suggested the possibility of 100 TPG telomerase activity being a prognostic factor for recurrence. Prospective studies will be necessary to clarify this matter.

Clinicopathological study of unilateral multiple breast cancer.

BACKGROUND: The tendency for breast cancer to form multiple lesions is important to consider when planning breast-conserving surgery. However, many unknowns remain regarding the pathology and prognosis of multiple breast cancer, and therefore it is clinically significant to investigate its clinicopathological properties. METHODS: Over the past 25 years, in the period between April 1972 and March 1997, we investigated the clinicopathological findings including the 5-year and 10-year survival rates of 66 patients treated for unilateral multiple breast cancer. RESULTS: Of the total of 1,334 female patients with unilateral breast cancer who underwent curative surgery at our hospital, we identified 66 (5.0%) patients with unilateral multiple cancer. The incidence of such cancer has been higher in recent years. Of the 66 patients, 50 (75.8%) were premenopausal, and the remaining patients were postmenopausal, but multiple cancer among postmenopausal women is a recent phenomenon. The ER positivity rate of the main lesion in patients with multiple breast cancer was 69.2% and that of PgR was 50.0%. The 5-and 10-year overall survival rate in all 66 patients with multiple breast cancer was 90.8% and 79.7%, respectively. CONCLUSION: In the past, multiple breast cancer was frequently identified in premenopausal women. However, the current findings indicate that its incidence among postmenopausal women has increased in recent years. In addition, prognoses were comparable for patients with multiple or solitary breast cancer, a relevant finding in the planning of breast-conserving surgery.

[Weekly administration of paclitaxel for advanced or metastatic breast cancer--short-course premedications for outpatients].

A phase II trial has demonstrated that paclitaxel (210 mg/m2/3 hr) showed a 33.3% response rate among anthracycline-resistant breast cancer patients in Japan. Recently, weekly dosing of paclitaxel has been demonstrated to be a well-tolerated, feasible and effective administration schedule. Standard premedication is commonly administered prior to treatment with paclitaxel. However, this regimen requires dexamethasone administration beginning at 12 to 14 hours prior to paclitaxel, which would not be convenient for outpatients. In this study, paclitaxel was administered by 1 hour intravenous infusion at a dose of 80 mg/m2 every week. Administration was continued for 3 weeks with a 1 week rest. A short course premedication schedule consisted of dexamethasone 20 mg i.v. (diluted in 50 ml normal saline, 1 hour prior to paclitaxel), and oral diphenhydramine 50 mg, H2-antagonist and anti-emetic agent i.v. (diluted in 50 ml normal saline, 30 minutes prior to paclitaxel). A total of 14 outpatients were enrolled in the study. There were 10 partial responders and no complete responders, and the overall response rate was 71.4%. No hypersensitivity reactions were observed, and grade 3/4 leukopenia occurred in 43% (6/14). Allopecia was observed in 4 patients, and peripheral neuropathy in 1 patient (both grade 1). Weekly administration of paclitaxel is effective and well-tolerated in patients with advanced or metastatic breast cancer, with a minimum of peripheral neuropathy. In addition to the above, no hypersensitive reaction in the short course premedication schedule suggests that this administration schedule is feasible for outpatients.

Molecular analysis of the h-warts/LATS1 gene in human breast cancer.

Loss of heterozygosity (LOH) on chromosome 6q is often observed in breast cancer, suggesting the existence of a putative tumor suppressor. Recently, a human homolog of the Drosophila warts tumor suppressor gene, h-warts/LATS1, was identified and mapped at chromosome 6q24-25.1. Mutation analysis of the h-warts/LATS1 was performed using 25 breast cancer tissues by RT-PCR SSCP analysis. Although LOH of the h-warts/LATS1 was found in one patient, no mutations were found. Two polymorphisms were found, but neither of them caused amino acid substitutions. Further investigations are necessary to elucidate the role of the h-warts/LATS1 gene in the carcinogenesis of breast cancer.

Absence of mutations in the analysis of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic human breast cancers.

The transforming growth factor-beta (TGFbeta) binds the type II TGFbeta growth factor receptor (TGFbetaRII) to inhibit the growth of most epithelial tissues. Most human colon and gastric cancers with microsatellite instability (MI) have frameshift mutations in polynucleotide repeats within the TGFbetaRII coding region; these mutations truncate the receptor protein and disable the serine/threonine kinase to produce TGF-beta resistance. To further investigate the type, frequency and tissue distribution of TGFbetaRII gene mutations, in this study, we examined 36 sporadic breast cancers. We previously produced eight intron based primer pairs for mutational analysis of the entire coding region of the TGFbetaRII gene. Using these primers, we developed protocols for polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of PCR products from genomic DNA samples of 36 breast cancer patients and we tested them for microsatellite instability (MI) at eight microsatellite loci. One case demonstrated MI (2.8%) and we found no mutations. These and other recent data indicate that TGFbetaRII mutations are essentially confined to colon and gastric cancers with MI. The narrow spectrum of tissues containing RII mutations illustrates the complexity of genetic checkpoints in human carcinogenesis.

[A case of recurrent breast cancer responding to long-term treatment with 5'-DFUR combined with MPA].

A 55-year-old woman with recurrent breast cancer treated with sequential mastectomies, chemo-and hormonal therapy of UFT, CPM and TAM, achieved remission. Six months later she was admitted with a diagnosis of carcinomatous pleurisy. A large pleural effusion was drained followed by administration of ADM, which improved her effusion and accompanying dyspnea. The effusion recurred but the patient desired outpatient treatment. Thus, we prescribed oral 5'-DFUR and MPA. One month later, her cough had improved and her sputum cytology was negative, while on chest radiograph the pleural effusion had decreased and the patch-like shadows in her right lung field had disappeared. She was considered as a case of PR. At one year and 3 months after starting concomitant 5'-DFUR and MPA the pleural effusion disappeared. The patient has received this outpatient treatment for 2 years without adverse reactions.

[Clinical significance of alpha(1----3)-L-fucosyltransferase activities in sera from patients with malignant diseases with a special reference to a potential tumor marker].

We measured alpha(1----3)-L-fucosyltransferase (alpha 13FT) activity in human plasma samples obtained from a group of 111 patients with malignant diseases, 86 patients with benign diseases, and 58 healthy controls using a newly developed assay method (Clin. Chem., 37: 2081-2086, 1991). The cutoff value was arbitrarily set at 73 units/ml (mean +/- 3SD of results for healthy controls). Forty-one of the 111 (36.9) plasma samples from patients with cancer showed high enzyme activity, and twelve of the 86 (13.6%) samples from patients with benign diseases were above the cutoff value. The levels of alpha 13FT were considerably high in samples obtained from the patients with esophagus, lung, liver and pancreatic and biliary cancer, and corresponding positive rates were 66.7, 64.7, 62.5 and 62.5%, respectively. The elevation of the enzyme activity was found in many samples from advanced cancer, whereas samples from patients with gastric and colon cancer in the clinical stage I showed high positive rates. No correlation was observed between the level of alpha 13FT and tumor--associated antigens such as carcinoembryonic antigen, CA19-9, and sialyl Tn (STN). These results suggest that alpha 13FT activity measured by the present assay method could have a potentiality for a new type of tumor marker.

[Changes in lymphocyte subsets with post-operative chemotherapy in breast carcinoma--a study of using two color analysis].

Thirty postoperative patients with breast cancer (stage I, II) were studied to clarify the changes of peripheral lymphocyte subsets by administration of anticancer drugs (UFT, cyclophosphamide (CPM]. The patients were divided into two groups: UFT (400 mg/day) group (n = 15) and CPM (100 mg/day) group (n = 15). Immunological investigation, in particular two color analysis of peripheral lymphocyte subsets, were carried out 30 days after treatment. Results from the investigation, there were no inhibitory effects on the total lymphocyte counts by UFT, whereas a promoting effect was observed on Ts (Suppressor T), and CD16+ (NK) subsets. On the other hand, CPM displayed an inhibitory tendency on the total lymphocyte counts, and also an inhibitory effect on Thi (Helper inducer T), and Tsi (Suppressor inducer T) subsets. These results suggest that the changes of lymphocyte subsets in response to above two drugs are different, which may be significant in determining treatment regimens.

[The effectiveness of radiation therapy in bone metastasis from breast cancer].

48 cases with bone metastasis from breast cancer were treated by radiation therapy. Result; 1) The effective ratio of radiation therapy on symptomatic relief of pain was 83%. 2) In 90% of effective cases, patients felt pain relief at 20 Gy. 3) For 3 of 7 cases which showed paralysis by vertebral metastasis, radiotherapy was very effective. 4) The patients with only bone metastasis have good prognosis. So, it is important radiotherapy is performed on different outlook.

[Hormone receptors (ER, PgR) as a prognostic factor in breast cancer].

To investigate the significance of the hormonal receptors (ER: estrogen receptors; PgR: Progesterone receptors) as prognostic factors in breast cancer, 213 patients with breast cancer (stages I-III) who were examined for both receptors and had not received adjuvant hormonal therapy have been studied so as to determine a disease-free survival rate. In stage I, the status of the hormonal receptors failed to show any statistically significant differences with regard to the disease-free curve. However, in patients in advanced stage, the presence of either PgR or both receptors positively correlated with the disease-free survival curve. In comparing the ER with the PgR as prognostic factors, the presence of the PgR seemed to be more important than the presence of the ER. These data suggest that the status of the hormonal receptors is considered to have prognostic significance.

[The concentration in the tissue and antitumor effect of anticancer drug--assessment of breast cancer with UFT or FT-207].

The correlation between intralesional 5-FU concentrations and the extent of antitumor effect with particular attention to histopathology was assessed in 30 patients with breast cancer. Therapy consisted of either UFT or FT-207 given preoperatively. Although the UFT-treated group showed a significantly higher intratumoral concentration of 5-FU, there was no intergroup difference in 5-FU levels in normal tissue. In addition, this greater concentration of intratumoral drug had no significant effect on therapeutic response; for both UFT and FT-207 treated groups, the histologic interpretation was rated as grade IIa. Regardless of which drug was used, when tumors were stratified according to histologic type, papillotubular carcinomas revealed the greatest tissue 5-FU levels. However the greatest histologic antitumoral responses were seen in scirrhous carcinomas; hence no correlation was seen here either. The results suggest that attainment of a high intratumoral 5-FU concentration is not reflected in a better histologic tumor response in patients receiving the above drug regimens.

[5-FU concentration in the tissues (tumor and lymph node) of breast cancer patients given preoperative administration of UFT and FT].

In 16 patients with breast cancer who were administered UFT or FT-207 (UFT: 9 cases, FT-207: 7 cases) for a were prior to surgery, we studied the concentrations of 5-FU in the blood and tumor tissues, and in normal and metastatic lymph nodes sampled during surgery. As a result, a high level of 5-FU was found in tumors, especially in metastatic lymph nodes, in the patients who were administered UFT. On the other hand, no significant difference was found between the 5-FU levels of blood in UFT- and FT-treated patients. These facts suggest that UFT can be expected to increase antitumor activity without side effects, especially in cases of metastatic lymph nodes.

[Effect of cyclophosphamide on immunological responses in patients with breast cancer relating to BRM (biological response modifiers)].

Cyclophosphamide (CPM) is widely used in patients with breast cancer as an adjuvant chemotherapy. On the other hand, it is a well-known fact that CPM-treated animals show an increased intensity of cell-mediated immunity such as DTH (delayed-type hypersensitivity) reactions. Recently, such functions of CPM have seemed to make it note worthy as a BRM. Therefore, in 26 postoperative patients with breast cancer, the effect of CPM on various immunological responses was investigated after administration of CPM (100mg/day) for a period of 30 days. Significant decrease of lymphocyte counts, B-cell percentages, and T gamma-cell percentages were observed. However, PPD skin test showed a tendency for increased reaction. Both OKT3+ lymphocytes and OKT 11+ lymphocytes increased significantly. However, an inhibitory effect of CPM on OKT8+ lymphocytes (suppressor/cytotoxic) was not observed. From the results of this study, increased intensity of DTH reactions by CPM was interesting in relation to BRM action, and the inhibitory effect of CPM on B-cells seemed to be connected with activated cell-mediated immunity.

[Clinical effect of Peplomycin on recurrent breast cancer].

Twelve patients with recurrent breast cancer were treated with Peplomycin monotherapy. Peplomycin was given intermittently with a dose of 10 mg intramuscularly twice a week. As side effects of Peplomycin, fever elevation in 75% (9/12), malaise in 67%, nausea and vomiting in 42%, anorexia in 42%, pulmonary toxicity in 8%, and loss of hair in 8%, were observed. Out of 8 evaluable cases, CR was obtained in 1, PR in 1, NC in 3, and PD in 3 cases, respectively.