Efficacy of postoperative adjuvant therapy for stage ilia breast cancer: Futraful vs futraful+tamoxifen for er-positive patients and futraful vs futraful + adriamycin for er-negative breast cancer

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.     

FDG-PET for the evaluation of tumor viability after anticancer therapy

To evaluate positron emission tomography with¹⁸F-fluorodeoxy glucose (FDG-PET) as an diagnostic tool to determine tumor viability after anticancer therapy, fourteen patients were examined by FDG-PET after the end of the treatment. The lesions with residual viable tumor cells showed higher uptake of FDG than surrounding normal soft tissue. The lesions, in which tumor viability was lost or very low, showed higher uptake of FDG in four cases and similar uptake to normal soft tissue in three cases. The residual increased uptake of FDG was considered to be caused by remaining tumor cells and/or inflammatory reaction to anticancer treatment. FDG-PET after anticancer treatment should be interpreted by considering the reaction due to the treatment and the partial volume artifact of PET caused by the limited spatial resolution.     

FDG-PET for predicting the prognosis of malignant lymphoma

To evaluate the usefulness of FDG-PET as a predictor of prognosis, 34 patients with untreated malignant lymphoma in the head and neck region were studied. After FDG-PET and treatment, they were observed from 15 to 50 months. Tumors which were aggressive and resistant to treatment tended to show high uptake of FDG. The survival rate of patients with high uptake of FDG, DAR > 8, was lower than the rate of the other patients. It is considered to be useful to add FDG uptake of the tumor to other prognostic factors for predicting the prognosis.     

Enrichment of generated murine osteoclasts

Biochemical and molecular studies of osteoclasts generally require cells in a reasonable degree of purity. The chicken has been extremely useful in this regard, as abundant avian osteoclasts can be generated in vitro entirely from pure populations of marrow macrophage precursors. Propagation of murine osteoclasts is, in contrast, far less efficients, demanding the presence of stromal cells. The aims of this study were to develop a method by which murine osteoclasts generated in culture, can be effectively enriched while maintaining viability and, to explore the mechanisms by which stromal cells promote murine osteoclast generation and survival. We find that 10⁶ fractionated murine marrow cells enriched, for marrow-residing colony-forming units (CFU-cs), yield 3000–4000 tartrate-resistant acid phosphatase (TRAP)-expressing multinucleated giant cells when cultured for 12 days with ST-2 stromal cells. These cells are osteoclasts as evidenced by their ability to pit bone slices, resorb radiolabeled bone particles, and generate cyclic AMP in response to calcitonin. Treatment of these generated osteoclast cultures with bacterial collagenase for 2 hours at 37° selectively removes virtually all ST-2 cells, yielding a >60% pure population of TRAP and calcitonin receptor-expressing cells, 90% of which are viable. These cells continue to respond to calcitonin and survive for 24 hours in the absence of ST-2 cells. We also found that murine osteoclast generation depends upon contact of osteoclast precursors with viable ST-2 cells. Furthermore, the stromal cells secrete macrophage colony-stimulating factor (CSF-1), and the anti-CSF-1 antibody 5A1 inhibits murine osteoclastogenesis. Exogenous CSF-1, in turn, partially overrides the anti-osteoclastogenic effect of 5A1. We conclude that (1) the purity of murine osteoclasts generated from bone marrow cells enriched for CFU-cs can be greatly enhanced by selective removal of associated stromal cells, and (2) both soluble and membraneresiding stromal cell factors are necessary for generation of murine osteoclasts.     

The impacts of breast conserving treatment and mastectomy on the quality of life in early-stage breast cancer patients

The quality of life (QOL) in 55 early-stage breast cancer patients after surgery was prospectively assessed using a newly developed Japanese QOL questionnaire: The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The impacts of breast conserving treatment (BCT) (22 cases) and modified radical mastectomy (MRM) (33 cases) on the QOL in those subjects were compared. The overall QOL scores were evaluated during four periods (before surgery, 0–2, 3–12, and 13–24 months after surgery). The mean scores of the four categories of the QOL-ACD (activity, physical condition, psychological condition, and social relationships) were also compared. The results demonstrated that a significant improvement was observed in the overall QOL scores among the three periods after surgery (0–2, 3–12, and 13–24 months) only in the BCT group (P<0.05). There were no significant differences between the two groups in the overall QOL scores during any of the three periods after surgery, and the mean score of the ‘psychological condition’ during 0–2 months period in the BCT group was significantly lower than that in the MRM group (P< 0.05).     

Effect of distance and population size on patient trips in a prefecture of Japan: Application of a transportation distribution model to the demand for and supply of health services

The gravity model, a method for analyzing transportation distribution in transportation engineering, was used to explain patient trips between ten health service regions in a Japanese prefecture. The OD (Origin-Destination) tables were constructed with zoning by regions, distinguishing between out- and inpatients. The observed trips were determined from the data of a survey conducted in 1992 that reported the locations of patient residences and chosen medical facilities. The base values used in the model calculations were the population size of each region and the road distance between the centers of regions. Problems of intrazonal trip were avoided by setting a mean intrazonal movement distance. This model was calibrated by the linear regression method with simultaneous validation by the index of correlation coefficients. The model was found to accurately simulate the effect of distance on the choice of medical facilities and the differences between the characteristics of in- and out-patients. The population value in use showed the relation not only with demand but also the supply of clinical services. It was suggested that the model presented here was useful in the allocation of medical resources and would help explain the relationship between suppliers and consumers of medical services.     

Serum tumor marker kinetics and the clinical course of patients with advanced breast cancer

Serum carcinoembryonic antigens (CEA), CA 15-3, and tissue polypeptide antigens (TPA) have been used in monitoring the clinical course of patients with breast cancer. However, recent reports have suggested that the serial levels of these markers during therapy do not always correlate with the response to therapy. To clarify the usefulness of the serial combination assay of these markers in monitoring the clinical course of patients during therapy, we investigated the relationship between the initial changes and the kinetic patterns of the markers after therapy and the objective responses. When an increase or decrease of over 20% in these markers is taken to be significant, then the initial changes in all three markers significantly correlated with the therapeutic responses (P<0.01). Five distinct kinetic patterns in the marker levels were observed. A paradoxical kinetic pattern of CEA and CA 15-3 levels — that is, an initial surge and subsequent drop — was seen in one-third of the responders. The TPA levels tended to exhibit a steady decline pattern in those responders. The sensitivity and specificity of the kinetic patterns to predict the clinical courses were significantly higher than those obtained from the analysis of initial changes. These findings thus suggest that adequate knowledge of the unique kinetics of each marker may help to make a more accurate prediction of the therapeutic responses.     

Serum fluoride as an indicator of occupational hydrofluoric acid exposure

Summary To define the relationship between ionic fluoride concentration in the serum of workers and the amount of hydrofluoric acid (HF) in the work environment, pre-and postshift serum and urine samples of 142 HF workers and 270 unexposed workers were examined. The maximum and minimum concentrations of HF in the air in each workshop varied from the mean by less than 30%. The pre-exposure levels of serum and urinary fluoride in HF workers were higher (P < 0.001) than the control values. This suggests that fluoride excretion from the body continues for at least 12 h. The postshift serum and urinary fluoride concentrations of these workers were significantly higher (P < 0.001) than the preshift concentrations. A good correlation (r = 0.64) was obtained between postshift serum fluoride and postshift urine fluoride. There was a linear relationship between mean serum fluoride concentration and HF concentration in the workshop. A mean fluoride concentration of 82.3 g/l with a lower fiducial limit (95%, P = 0.05) of 57.9 g/l was estimated to correspond to an atmospheric HF concentration of 3 ppm. This is the maximum allowable environmental concentration recommended by the Japanese Association of Industrial Health, and it is also the threshold limit value suggested by the American Conference of Governmental Industrial Hygienists. The results demonstrate that exposure to HF can be monitored by determining the serum fluoride concentration.     

The expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase associates with angiogenesis in epithelial ovarian cancer

Background The object of this study is to clarify the association of an angiogenic factor, PD-ECGF (platelet-derived endothelial cell growth factor/thymidine phosphorylase), with clinicopathologic factors, in this case tumor angiogenesis, in epithelial ovarian cancers. Methods Tumor specimens were obtained at the time of surgery from the primary lesion in 60 patients with epithelial ovarian cancer. Histologic cell types were assigned to tumors according to the World Health Organization classification: 26 were classified as serous adenocarcinoma, 15 as endometrioid adenocarcinoma, 9 as mucinous adenocarcinoma, 9 as clear cell carcinoma, and 1 as undifferentiated carcinoma. Surgical staging was based on the international Federation of Gynecology and Obstetrics (FIGO) staging system: 16 were stage I, 6 were stage II, 34 were stage III, and 4 were stage IV. Expression of PD-ECGF was evaluated by immunohistochemical staining. Microvessel density was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. Results Stroma cells stained more strongly than cancer cells (80% vs. 33%). The immunopositivity of PD-ECGF in stroma cells was higher in cases of advanced cancer. Expression of PD-ECGF in mucinous adenocarcinomas was significantly higher than that in serous adenocarcinomas, while PD-ECGF expression in clear cell carcinomas was significantly lower. The microvessel density in the cases with marked PD-ECGF-positive stroma cells was significantly higher than that in the cases with absent/minimal PD-ECGF-positive stroma cells (P<0.05). Conclusion The expression of PD-ECGF may play a crucial role in the promotion of angiogenesis in epithelial ovarian cancers.     

Inhibition of tumor growth and metastasis by angiogenesis inhibitor TNP-470 on breast cancer cell lines in vitro and in vivo

Antitumor and antimetastatic activity of the angiogenesis inhibitor O-(chloroacetyl-carbamoyl) fumagillol (TNP-470), a semisynthetic analogue offumagillin, was evaluated in breast cancer cell lines. In an in vitro MTTassay, after 72 hrs continuous exposure to TNP-470, growth inhibition wasobserved in all seven cell lines of murine (JYG-A, JYG-B, DD-762, andBALB/c-MC) or human (KPL-1, MDA-MB-231, and MKL-F) origin, in which the50% inhibitory concentrations (IC₅₀) at 72 hrstreatment were 4.6, 4.4, 4.6, 10.1, 35.0, 25.3, and 33.4 µg/ml,respectively. In an in vivo assay using JYG-A, JYG-B, KPL-1, and MDA-MB-231cells by orthotopic (right thoracic mammary fat pad) transplantation infemale nude mice, TNP-470 at 30 or 50 mg/kg body weight was injected s.c.every other day from the day of tumor cell inoculation until the end of theexperiment. The inhibitory effect on primary tumor growth was obtained inall four cell lines in a dose-dependent manner. In the 50 mg/kgTNP-470-treated group, the reductions in tumor weight of the JYG-A, JYG-B,KPL-1, and MDA-MB-231 cells with respect to the controls were 50%,30%, 4%, and 49%, respectively. Metastasis was seen inthe JYG-A, JYG-B, and KPL-1 cells. The numbers of mice bearing pulmonarymetastases of JYG-A and JYG-B cells and regional axillary lymph nodemetastases of KPL-1 cells were reduced, and TNP-470 at the 50 mg/kg dose toKPL-1 cells significantly reduced lymph node metastases compared with thecontrol. Although the weight gain was retarded in the TNP-470-treated mice,weight loss was not seen. TNP-470 was highly effective in the treatment ofbreast cancer cells. These results suggest that the clinical use of TNP-470may be a promising treatment for breast cancer patients.