Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens.

BACKGROUND: This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy. PATIENTS AND METHODS: Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH. RESULTS: Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%). CONCLUSIONS: Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.

Pregnancy outcomes in women treated with elective versus ultrasound-indicated cervical cerclage.

OBJECTIVE: To compare pregnancy outcomes in women at risk for pregnancy loss treated with elective versus ultrasound-indicated placement of cerclage. METHODS: A retrospective cohort study was performed on two groups of patients with singleton gestations. The first group consisted of women at risk for pregnancy loss who were treated with an elective cerclage, while the second group was managed conservatively and followed with serial transvaginal cervical sonography and transfundal pressure. An emergency cerclage was placed in women in the second group when the endocervical canal length shortened to < 20 mm, either spontaneously or in response to transfundal pressure. The two groups were compared with respect to maternal demographics, obstetric and gynecological history, and gestational age, both at time of cerclage placement and delivery. RESULTS: A total of 138 patients were identified. Eighty-one patients were treated with an elective cerclage and 57 with an ultrasound-indicated cerclage. Patients treated with elective cerclages were older (32 versus 27 years, p = 0.0003), more commonly white (56.8% versus 38.6%, p = 0.0380), less commonly nulliparous (23.5% versus 43.9%, p = 0.0063), and more often private patients (92.6% versus 28.1%, p < 0.0001). A history of previous treatment with cerclage (45.7% versus 10.5%, odds ratio (OR) 0.2, 95% confidence interval (CI) 0.1-0.4) and one prior midtrimester loss (53.1% versus 33.3%, OR 0.4, 95% CI 0.2-0.9) were also more common in the elective versus ultrasound-indicated cerclage group. However, there was no difference in the rates of previous preterm delivery, two midtrimester losses, two terminations of pregnancy, in utero diethylstilbestrol exposure, uterine anomalies, history of cone biopsy or parity. As expected, gestational age at placement of cerclage was significantly earlier in the elective group (13.0 versus 20.0 weeks, p < 0.0001). The median (range) gestational age at delivery (37 (15-41) versus 37 (17-41) weeks, p = 0.90), the number of early (< 25 weeks) losses (9.9% versus 8.8%, OR 1.6, 95% CI 0.3-7.9), and preterm deliveries (< 37 weeks) (35.8% versus 36.8%, OR 1.1, 95% CI 0.4-3.2) were similar in the elective and ultrasound-indicated cerclage patients, respectively. CONCLUSION: In patients at risk for pregnancy loss, placement of cervical cerclages in response to ultrasonographically detected shortening of the endocervical canal length is a medically acceptable alternative to the use of elective cerclage.

GR122311X (ranitidine bismuth citrate), a new drug for the treatment of duodenal ulcer.

BACKGROUND: Ranitidine bismuth citrate (GR122311X) is a new drug which offers potential benefits in healing duodenal ulcers and prevention of relapse. METHODS: This randomized, multi-centre double-blind study of 1620 patients compared the effect of 4 weeks of treatment with GR122311X 200 mg b.d. (n = 401), 400 mg b.d. (n = 404) or 800 mg b.d. (n = 404) or ranitidine hydrochloride 150 mg b.d. (n = 411) on the rates of duodenal ulcer healing and of overall success (ulcers healed and remaining ulcer free in the 24-week follow-up phase). RESULTS: All four treatments were equally effective at ulcer healing (79%, 85%, 84% and 81% of patients, respectively). GR122311X 400 mg b.d. (38%) and 800 mg b.d. (37%) were significantly more effective than ranitidine hydrochloride 150 mg b.d. (32%) with respect to overall success (P = 0.050 and P = 0.030, respectively) but there was no difference with GR122311X 200 mg b.d. (31%). GR122311X caused effective, dose-related suppression of H. pylori (47%, 61% and 74%); H. pylori eradication rates were 18%, 21% and 22%. GR122311X was safe and well tolerated, with an adverse event profile similar to that of ranitidine hydrochloride 150 mg b.d. Median week 4 trough plasma bismuth levels were 1.3 ng/mL, 2.3 ng/mL and 3.3 ng/mL with GR122311X 200 mg b.d., 400 mg b.d. and 800 mg b.d. respectively. No individual plasma bismuth concentrations were of clinical concern. CONCLUSIONS: GR122311X is a safe and effective ulcer healing drug, and provides a platform on which anti-H. pylori therapy can be based.

Dose-response study with high-dose inhaled salmeterol in healthy subjects.

A double-blind, placebo-controlled, cross-over study in 10 healthy male subjects has been carried out to investigate the non-pulmonary effects of single inhaled doses of salmeterol 100 micrograms, 200 micrograms and 400 micrograms and salbutamol 400 micrograms from a metered-dose inhaler. At all doses tested, salmeterol produced statistically significant changes in pulse rate, tremor, blood glucose and plasma potassium concentrations, compared with placebo. All changes were dosed related. A number of dose-related adverse events including tremor, awareness of heart beat and headache were reported after salmeterol administration.

Effects of one year's treatment with ranitidine and of truncal vagotomy on gastric contents.

Fifteen patients with peptic ulcer underwent 24 hour studies of gastric contents: before and on completing six weeks' treatment with oral ranitidine 150 mg bd, twice on maintenance treatment for nine to 12 months and one month after stopping the drug. For comparison, 11 patients underwent identical 24 hour studies three to 38 months after truncal vagotomy for duodenal ulcer. During treatment with ranitidine median 24 hour intragastric pH, nitrate concentration, and counts of total and nitrate reducing bacteria increased significantly regardless of dietary nitrate content; there was no significant increase in the median day time concentration of N-nitroso compounds. Despite these changes, an acid tide at some point in each 24 hour study period prevented persistent bacterial colonisation of the stomach. There were no significant differences between the biochemical and microbiological changes recorded during one year of treatment with ranitidine, and the observations on patients after truncal vagotomy. One month after stopping one year's treatment with ranitidine all variables examined returned to pretreatment levels. Treatment with ranitidine or vagotomy was associated with significant positive correlations among pH, nitrate concentration and bacterial counts. Correlations between pH and N-nitroso compound concentration and between concentrations of nitrite and N-nitroso compounds were not significant.