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.     

Low grade amplification of MDM2 gene in a subset of human breast cancers without p53 alterations

MDM2 protein is thought to bind to p53 tumor suppressor protein leading to inhibition of p53-mediated transactivation. Amplification of the MDM2 gene has been frequently observed in human sarcoma, and relevant overexpression of the MDM2 protein is assumed to contribute to tumorigenesis through inactivation of the p53 function. In order to determine whether MDM2 amplification plays a role in the development of human breast cancer without genetic alteration of p53, we analyzed, MDM2 gene amplification by quantitative hybridization and genetic alteration of p53, in 32 primary tumors and 26 metastatic lymph nodes. Low grade amplification of the MDM2 gene (2-6 fold) was observed in four cases, none of which showed even subtle genetic alterations of p53 or loss of alleles on 17p. Moreover, in three of the four cases with MDM2 gene amplification, the level of gene amplification in the metastatic lymph nodes was slightly higher than that in the primary tumors. These results, taken together with previous findings, suggest that a subset of breast cancers without genetic alteration of p53 may also arise by inactivation of the p53 function through interaction with the overexpressed MDM2 protein induced by gene amplification.     

Total Esophagectomy versus Proximal Esophagectomy for Esophageal Cancer at the Cervicothoracic Junction

To investigate the adequate extent of esophagectomy and lymphadenectomy for an esophageal cancer localized at the cervicothoracic junction, the mortality and morbidity rates, survival rates, and patterns of recurrence were retrospectively analyzed in two groups—14 patients who underwent total esophagectomy with or without laryngectomy and 15 patients who underwent proximal esophagectomy with or without laryngectomy—at Kurume University Hospital from 1981 to 1996. Proximal esophagectomy with or without laryngectomy resulted in a lower hospital mortality rate and better overall survival for patients who underwent curative esophagectomy compared with total esophagectomy with or without laryngectomy. Multivariate analysis indicated that the extent of esophagectomy (total esophagectomy versus proximal esophagectomy) was not a prognostic factor. The incidence of recurrence was not different between the two groups. Lymph node metastasis or recurrence from such esophageal cancers was localized to the neck and upper mediastinum. For an esophageal cancer localized at the cervicothoracic junction, therefore, proximal esophagectomy with or without laryngectomy and with cervical and upper mediastinal lymphadenectomy could be better indicated for preselected patients.     

Intensification of antitumor effect by T helper 1-dominant adoptive immunogene therapy for advanced orthotopic colon cancer.

PURPOSE: T helper (Th) 1/Th2 balance, controlled by Th1 or Th2 cells producing cytokines, plays important roles in antitumor immunity. Interleukin-18 (IL-18) can act together with IL-12 in promoting the generation of IFN-gamma producing Th1 cells. The goal of this study was to determine whether cytotoxic T lymphocyte (CTL) secreted in a murine IL-18-induced Th1-dominant state inhibited the development of primary tumors and synchronous liver metastases in orthotopic colon cancer model. EXPERIMENTAL DESIGN: Murine IL-18 gene was transduced into activated T lymphocytes by an adenovirus vector encoding IL-18 (AdIL-18) liposome complex method. Efficacy of adoptive immunogene therapy using AdIL-18 with or without IL-12 was tested in advanced orthotopic xenograft of murine colon cancer. To elucidate the mechanism responsible for the adoptive immunogene therapy, serum IL-4, IL-6, IFN-gamma, and tumor necrosis factor alpha production in Th1/Th2 cytokine balance and quantification of tumor vascularity were investigated. RESULTS: By a modified method of adenoviral gene transduction, T lymphocytes achieved efficient IL-18 production without cell toxicity. Against orthotopic colon cancer, when combined with low dose of recombinant (r) IL-12 (AdIL-18-CTL/rIL-12), the therapeutic efficacy showed much smaller tumors with no liver metastases and no disseminated tumors. There was a significant difference in the volume of primary tumors and the number of liver metastases compared with the group treated with AdIL-18-CTL alone or other group (P < 0.01). In addition, the median survival time of the group treated with AdIL-18-CTL was 53.7 +/- 5.8 days and that of AdIL-18-CTL/rIL-12 was 78.4 +/- 6.1 days, which was also a significant difference (P < 0.01). These antitumor mechanisms were involved with Th1-dominant response in serum Th1/Th2 cytokine balance and suppression of neovascularization at primary tumor site. CONCLUSION: These data suggest that a strategy of Th1/Th2 balance-based adoptive immunogene therapy might be useful for advanced cancer patients.     

Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy.

PURPOSE: To assess the predisposing factors and clinical characteristics of pelvic insufficiency fractures (PIF) in postmenopausal women with pelvic irradiation. MATERIAL AND METHODS: A total 335 postmenopausal patients with cervical cancer of the intact uterus treated with radiation therapy between 1983 and 1998 were reviewed. Total external dose was delivered between 45 and 50.4 Gy with parallel opposed anteroposterior portals. Total brachytherapy dose at point A was delivered between 10 and 36 Gy. PIF were diagnosed by bone scintigraphy and confirmed by computed tomography. The cumulative incidence of symptomatic PIF was estimated by actuarial methods. Potential risk factors (age, weight, type II diabetes, delivery, menopause, total external dose, total brachytherapy dose) were assessed. RESULTS: Fifty-seven (17.0%) of 335 patients were diagnosed as having PIF. Forty-seven patients were symptomatic and ten were asymptomatic. Parameters carrying a significant association with PIF were body weight 49 kg or below (P=0.044) in stepwise logistic regression analysis. The cumulative incidence of symptomatic PIF at 5 years was 17.9% calculated by the Kaplan-Meier method. A body weight of 49 kg or below and more than three deliveries were identified as having a significant effect on symptomatic PIF in univariate analysis (P=0.021, P=0.003, log-rank test) and Cox life table regression analysis (P=0.038, P=0.013). Five patients required narcotic agents and eight patients required hospital admission. CONCLUSIONS: We should consider reducing the dose contribution to the sacrum and sacroilac joints, without underdosing the tumor, especially in postmenopausal women with many deliveries or low body weight.     

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.     

Characterization of antimutagenic mechanism of 3-allyl-5-substituted 2-thiohydantoins against 2-amino-3-methylimidazo[4,5-f]quinoline.

3-Allyl-5-substituted 2-thiohydantoins (ATH-amino acids) derived from allyl isothiocyanate and amino acids can inhibit the mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the Salmonella assay. In this report, we studied possible mechanisms for the inhibition using rat liver S9 in assays for ethoxyresorufin O-deethylase (EROD), a marker activity for cytochrome P450 1A (CYP1A), which activates heterocyclic amines, and the Salmonella assays with the direct-acting mutagen 2-hydroxyamino-3-methylimidazo[4,5-f]quinoline (N-hydroxy-IQ). Quantitative analysis of ATH-amino acids and IQ during incubation with rat liver S9 fraction by HPLC showed that ATH-amino acids could act as S9-inhibitors, thereby inhibiting metabolic activation of IQ. Among the tested ATH-amino acids, ATH-Phe, ATH-Trp, ATH-Leu and ATH-Val showed a dose-dependent inhibition of EROD activity. ATH-Gly, ATH-Glu, and ATH-Asp behaved as blocking agents toward N-hydroxy-IQ, but exhibited no inhibition of EROD activity.     

Allergic symptoms and microflora in schoolchildren.

We studied 867 junior high school children and administered a questionnaire documenting allergic symptoms and environmental variables, and measured Immunoglobulin E serum levels and the immunoglobulin G titers of serum antibody to microflora. A total of 716 subjects were ultimately used for statistics; those with at least two of the following allergic symptoms: asthma, rhinitis, eczema, or food allergy, showed significantly higher IgG titers to Bactroides vulgatus than other groups. This finding suggests that a species of the Bacteroides genus of the intestinal microflora tends to affect the gut issues, but further studies are needed to clarify this.     

Long-lasting renal dysfunction following tacrolimus induction therapy in ulcerative colitis patients

Although tacrolimus (TAC) has remarkable effects in ulcerative colitis (UC) patients when given as remission induction therapy, some can develop renal dysfunction during TAC administration, resulting in withdrawal, though related details remain poorly understood. This study was conducted to determine the impact of oral TAC on renal function for remission induction therapy in UC patients. Fifty-five patients (10 elderly, 45 non-elderly) with UC and treated with oral TAC at our hospital were retrospectively evaluated. Renal function was assessed using estimated glomerular filtration rate (eGFR). Although a high clinical response to TAC was seen in both elderly and non-elderly, a decline in eGFR was noted in nearly all patients regardless of age, with a maximum change of −34.4% from the baseline value at week 11. Furthermore, eGFR decline recovered quickly after TAC discontinuation, though did not return to the baseline at two years following cessation. The rate of eGFR change at week 12 was significantly associated with patient age (β = −0.3242, p = 0.0103) and peak serum trough level during TAC treatment (β = 0.3563, p = 0.0051). Furthermore, the rate of decline in eGFR was significantly greater during treatment with TAC in the elderly as compared to non-elderly, with a large difference in eGFR decline rate between those groups also noted at two years after withdrawal of treatment. Careful attention to renal function when administering oral TAC for UC is important and changes in eGFR should be monitored closely in elderly patients even after treatment cessation.