In human atrial and ventricular myocardium, the muscarinic cholinoceptor (M-cholinoceptor) populations were characterized by means of radioligand binding (with [N-methyl-3H]-scopolamine ([3H]-NMS) as the ligand) and functional experiments (negative inotropic effect of carbachol on isolated electrically driven right atrial and left papillary muscle preparations). (1) Binding of [3H]-NMS to human atrial and ventricular membranes was rapid, reversible and saturable (KD-values: 0.5-1.0 nmol/l). The maximal number of [3H]-NMS binding sites, however, was approximately 2.5-fold higher in right and left atrial membranes (200-250 fmol [3H]-NMS specifically bound/mg protein) than in right and left ventricular membranes (80-100 fmol/mg protein). (2) M-cholinoceptor antagonists inhibited [3H]-NMS binding to right atrial and left ventricular membranes with steep, monophasic competition curves indicating interaction with a single class of binding sites. In both tissues the order of potency was: atropine greater than AF-DX 116 greater than hexahydrosiladifenidol (HHSiD) greater than pirenzepine. (3) On isolated electrically driven right atrial and left papillary muscle preparations (with force of contraction enhanced by 10(-5) mol/l isoprenaline), carbachol (10(-8)-10(-4) mol/l) caused concentration-dependent decreases in force of contraction; the pD2-value for carbachol was 6.65 +/- 0.09 (n = 8, atria) and 6.62 +/- 0.08 (n = 10, papillary muscles). In both tissues M-cholinoceptor antagonists antagonized the negative inotropic effect of carbachol with an order of potency: atropine greater than AF-DX 116 greater than HHSiD greater than pirenzepine, identical to that obtained in radioligand binding experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

The combination of capecitabine and vinorelbine can be administered with manageable toxicity and showed significant efficacy for patients with metastatic breast cancer even after failure of a anthracycline- and/or taxane-based therapy.

The purpose of this randomized phase III trial was to study whether medroxyprogesterone acetate (MPA) maintenance treatment prolongs the time to progression in advanced breast cancer patients responding to an induction chemotherapy. Patients with progressive advanced breast cancer previously untreated with anthracylines and progestins were given epirubicin (30 mg/m2) and ifosfamide (2 g/m2) on days 1 and 8 at 3-weekly intervals. Patients without disease progression after 6 cycles of chemotherapy were randomly assigned to receive, until progression, either no treatment or MPA at a daily total dose of 500 mg. Ninety patients were randomized: 46 to the MPA arm and 44 to the observation arm. Median time to progression was longer in the MPA arm: 4.9 months versus 3.7 months in the intent-to-treat analysis (p = 0.02), and 4.9 months versus 3.0 months in the secondary efficacy analysis (p = 0.012). Seven patients were removed from MPA due to side effects. The changes in patient-rated quality of life scores were similar in both groups. The median length of survival from randomization was 17.4 months for patients receiving MPA and 18.3 months for patients randomized to observation (p = 0.39). In conclusion, in patients with advanced breast cancer achieving remission or non-progression with 6 cycles of epirubicin and ifosfamide chemotherapy, MPA maintenance treatment led to a significant, though modest, prolongation of the time to progression without affecting overall survival of the study patients.

Summary:The purpose of this prospective trial was to study a combined-modality treatment including local consolidation by surgery or radiotherapy and high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell (PBSC) transplantation. In all, 48 patients with oligometastatic breast cancer amenable to local treatment after induction chemotherapy with epirubicin and cyclophosphamide or paclitaxel and cisplatin, depending on prior adjuvant chemotherapy, were enrolled. The median follow-up was 41 months (range, 7-85 months). PBSC were collected in 47 patients, and 40 received one or two courses of HDC. Local therapy was given in 37 patients. No treatment-related deaths occurred. Of 47 evaluable patients, 36 (75% of intention-to-treat population) had no evidence of disease or complete remission after completion of therapy. Six patients (12.5%) had partial response, two patients (4%) no change, and three patients (6%) progressive disease. The median time to progression and overall survival was 17.5 (95% confidence interval (CI), 14-21 months) and 42.2 months (95% CI, 33-52 months), respectively, and 27% of patients were progression free after 5 years. In conclusion, patients with oligometastatic breast cancer can be treated safely with this combined modality protocol with promising relapse-free survivals.

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602 Background: Addition of trastuzumab (Roche; T) to chemotherapy (CT) has improved outcomes in patients (pts) with HER2+ breast cancer at all stages, including locally advanced and metastatic disease. Anti-HER2 re-treatment with T is an increasingly used therapy option for the treatment of recurrent/metastatic breast cancer (MBC). However, limited data on T re-treatment is currently available. Methods: Patients with locally recurrent and/or MBC who received T re-therapy were included in this non-interventional study. Among 232 pts enrolled at 121 sites in Germany, 174 pts (33 locally recurrent disease, 141 MBC) were already sufficiently documented to be analyzed for efficacy of T re-therapy in this ongoing study. Progression-free survival (PFS) was assessed by the investigator. Results: The median disease-free interval (calculated from the time of resection of the primary tumor to diagnosis of local recurrence/MBC) was 3.1 years. Median duration of re-therapy with T was 9.3 months. The median PFS of all patients was 10.1 months (95% confidence interval (CI), 8.5 to 13.1). PFS for pts with only locally recurrent disease (n= 33) was 23.6 months. PFS for MBC pts (n=141) was 8.9 months (95% CI, 7.4 to 10.6). For pts with visceral metastases (n=96) a PFS of 8.0 months compared to 10.1 months in patients with only non-visceral (n=45) was recorded. 104 pts were re-treated with T + CT (>70% paclitaxel, vinorelbine, capecitabine or docetaxel alone; PFS= 9.3 months), 26 pts with T + hormonal therapy (HT) (mostly anastrozole, fulvestrant, exemestane, letrozole or tamoxifen; PFS=10.1 months), 24 pts with T+CT+HT (PFS= 19.9 months) and 20 pts with T monotherapy (PFS= 9.4 months). Conclusions: This study provides clinical evidence that re-application of T in combination with either CT, HT or alone is effective in the routine treatment of patients with MBC and/or locally recurrent disease. The benefit observed for pts receiving first-line treatment with T in combination with taxane in pivotal trials as well as recently published data seems comparable to the presented results of pts receiving T re-therapy.