Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.     

Excitotoxic lesions of the pedunculopontine tegmental nucleus disinhibit orofacial behaviours stimulated by microinjections of d-amphetamine into rat ventrolateral caudate-putamen

Data are presented which support the hypothesis that the pedunculopontine tegmental nucleus serves as an output station for the striatum and, in particular, has a role in the expression of behaviour stimulated from the ventrolateral caudate-putamen, a rodent homologue of the primate putamen. Rats received either bilateral ibotenate or sham lesions in the pedunculopontine tegmental nucleus and bilateral cannulation of the ventrolateral caudate-putamen. Oral motor activities were observed following microinjection of 5.0, 10.0 and 20.0 g d-amphetamine (and vehicle-only control) into the ventrolateral caudate-putamen. As expected, orofacial behaviours such as biting and licking were observed in sham-lesioned rats following this treatment, but pedunculopontine tegmental nucleus-lesioned rats exhibited an increase in the incidence of these oral motor behaviours at all doses of amphetamine compared with the controls. This increase was the product of changes in the duration and number of times in which they engaged in oral motor behaviours, but not the latency to initiate them. There was no change in the normal oral motor activities associated with grooming. Histological analysis showed that ibotenate lesions destroyed both cholinergic and non-cholinergic neurones in the pedunculopontine tegmental nucleus. These data indicate that loss of the pedunculopontine tegmental nucleus disinhibits oral motor behaviours stimulated from the ventrolateral caudateputamen by d-amphetamine and are discussed in terms of their implications for understanding the relationships between striatal outflow and structures in the pons.     

Self-Directed Treatment of Intermittent Heartburn: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Evaluation of Antacid and Low Doses of an H(2)-Receptor Antagonist (Famotidine)

BACKGROUND: Heartburn, a common symptom, is self-treated with oral antacids. Efficacy of antacids has not been demonstrated for individual, spontaneous heartburn episodes. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group study of self-directed treatment for episodic heartburn comparing famotidine (FAM) 5, 10, or 20 mg and antacid (11 mEq ANC) to placebo (PBO) during a 4-week period. Twenty-nine US investigators enrolled a total of 565 outpatients, ages 18--81 years (mean 44.1 years) with heartburn but not seeking care for heartburn. Treatment of spontaneous heartburn episodes was permitted as needed, up to twice daily, with self-administered test drug. An open-label, backup antacid was provided to use if test drug did not provide adequate relief. Patients assessed heartburn relief hourly and recorded use of backup antacid. Relief was defined as complete relief of symptoms without the use of backup antacid. RESULTS: The media proportion of episodes relieved was: PBO, 41%; FAM 5 mg, 59%, 0.05 less-than-or-equal p < 0.10; FAM 10 mg, 70%, p < 0.001; FAM 20 mg, 69%, p < 0.001; antacid, 62%, p < 0.05 (p-values versus PBO). Supplemental analyses incorporating time to relief confirmed that famotidine and antacid provided more rapid and more frequent relief than placebo (odds ratio for relief relative to PBO: FAM 5 mg, 1.55, p = 0.003; FAM 10 mg, 1.94, p < 0.001; FAM 20 mg, 2.13, p < 0.001; antacid 1.57, p = 0.003). The tolerability profile was similar with famotidine, antacid, and placebo. CONCLUSIONS: The positive results with antacid demonstrated for the first time the efficacy of antacid in self-treatment of individual heartburn episodes and provided internal validation of this study paradigm. Patients in this study self-medicated effectively using low doses of famotidine on an as needed basis for spontaneous episodes of heartburn.     

Professor Giuseppe Satta,MD 1942–1994 Associate Editor European Journal of Epidemiology

Obituary

Professor Giuseppe Satta, MD 1942–1994 Associate Editor European Journal of Epidemiology     

Patient Compliance and its Impact on Treatment Outcomes

Despite an abundance of literature that assesses medication compliance associated with specific diseases, its impact on patient outcomes remains poorly characterised, perhaps due to the complexity associated with its influence and measurement. Much of the previous research includes end-points that were reflective of the duration and pattern of medication use; the value of which is questionable. In fact, the accuracy of compliance data remains highly controversial due to the difficulties associated with its measurement. Monitoring, by itself, may result in minor improvements in medication compliance; monitoring that is coupled to a meaningful clinical outcome that patients can self-measure results in enhanced compliance.Disease management programmes frequently contain interventions to impact compliance. Disease management programme developers interested in positively affecting compliance should incorporate patient self-monitoring methods into their compliance interventions.     

Minimally invasive cardiac surgery for removal of the greater saphenous vein

Objective

To determine if saphenous vein required for coronary bypass could be quickly, easily and safely removed with a minimally invasive technique.

Design

A consecutive series.

Setting

A university centre.

Material and Methods

In cadavers, a standard mediastinoscope was used to remove segments of the greater saphenous vein. Thigh segments, superior leg segments and ankle segments were removed. Fifteen minutes were allowed for removal of a segment.

Results

Segments of vein 15 to 17 cm long could be removed. One segment could not be removed within 15 minutes. Thigh segments were easy to remove, calf segments were the most difficult. There were no avulsed side branches. All incisions were less than 5 cm long.

Conclusions

Saphenous vein can be harvested quickly and safely by a minimally invasive method. Lower extremity complications may be reduced and long-term patency improved with this in-situ technique of vein removal.     

Evaluation of breast cancer risk assessment techniques: a cost-effectiveness analysis.

OBJECTIVE: Assess the effectiveness and cost-effectiveness of using biomarkers and risk assessment tools to stratify women for breast cancer preventive interventions.METHODS: A Markov model was developed to compare risk management strategies for high-risk women considering chemoprevention. Annual screening is compared to the use of chemoprevention for all women and the use of risk assessment technologies to stratify patients for chemoprevention. The biomarker atypia was used to stratify women by risk. Random fine-needle aspiration (rFNA) and ductal lavage (DL) were evaluated and compared as the risk assessment tools used to discover atypia. Sensitivity analyses explore assumptions regarding the prognostic and predictive characteristics of atypia, both the relative breast cancer risk and benefit from chemoprevention women with atypia incur.RESULTS: Risk assessment strategies using rFNA or DL in combination with chemoprevention are found to be cost-effective (<$50,000 per life year saved) in high-risk groups under most scenarios. Both strategies were more effective and less costly in younger cohorts. Effectiveness of the risk assessment strategies increased when higher risk and increased benefit from chemoprevention were associated with atypia. Within the scenarios tested, rFNA is less costly than DL.CONCLUSION: rFNA and DL appear to be cost-effective in high-risk women, assuming women with detected atypia choose tamoxifen. The tools are largely effective for women who are not motivated to take tamoxifen but would be if atypia were found. As biomarker risk assessment tools better predict the risk of breast cancer and or benefit of interventions, their cost-effectiveness increases.     

Increased Fas expression reduces the metastatic potential of human osteosarcoma cells.

PURPOSE: The process of metastasis requires the single tumor cell that seeds the metastatic clone to complete a complex series of steps. Identifying factors responsible for these steps is essential in developing and improving targeted therapy for metastasis. Resistance to receptor-mediated cell death, such as the Fas/Fas ligand pathway, is one mechanism commonly exploited by metastatic cell populations. EXPERIMENTAL DESIGN AND RESULTS: LM7, a subline of the SAOS human osteosarcoma cell line with low Fas expression, was selected for its high metastatic potential in an experimental nude mouse model. When transfected with the full-length Fas gene (LM7-Fas), these cells expressed higher levels of Fas than the parental LM7 cells or LM7-neo control-transfected cells. These cells were also more sensitive to Fas-induced cell death than controls. When injected intravenously into nude mice, the LM7-Fas cell line produced a significantly lower incidence of tumor nodules than control cell lines. Lung weight and tumor nodule size were also decreased in those mice injected with LM7-Fas. Levels of Fas were quantified in osteosarcoma lung nodules from 17 patients. Eight samples were Fas negative, whereas the remaining 9 were only weakly positive compared with normal human liver (positive control). CONCLUSIONS: Our results demonstrate that altering Fas expression can impact the metastatic potential of osteosarcoma cells. We conclude that the increase of Fas on the surface of the LM7 osteosarcoma cells increased their sensitivity to Fas-induced cell death in the microenvironment of the lung, where Fas ligand is constitutively expressed. Thus, loss of Fas expression is one mechanism by which osteosarcoma cells may evade host resistance mechanisms in the lung, increasing metastatic potential. Fas may therefore be a new therapeutic target for osteosarcoma.