Molecular determinants of cetuximab efficacy.

PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.     

Effectiveness of needle and syringe programmes for preventing HIV transmission

Objective: To examine the effectiveness of needle and syringe programmes (NSPs) in preventing HIV transmission among injecting drug users (IDUs).Methods: An ecological study design was used to determine change in HIV prevalence among injecting drug users between cities with and without NSPs. Several data sources, such as electronic journal databases, surveillance reports, websites, and index review of relevant journals, were used to identify studies of HIV seroprevalence among IDUs, and presence of NSPs. The rate of change in HIV prevalence was estimated by regression analysis.Results: There were 778 years of data from 99 cities globally included in the analysis. HIV prevalence decreased by 18.6% per annum in cities that introduce NSPs, and increased by 8.1% in cities that had never introduced NSPs (mean difference −24.7% [95% CI: −43.8, 0.5%], P=0.06). The mean difference was –33% when comparison was weighted to one over the variance of the regression estimator (29% decrease in cities with NSPs and 5% increase in cities without NSPs, P<0.001). When analysis was restricted to cities with first HIV seroprevalence less than 10%, the average annual change in seroprevalence was 18% lower in cities with NSPs (P=0.03).Conclusions: Despite the inherent limitations within an ecological study design, the study provides additional evidence that NSPs reduce transmission of HIV infection. The rapid spread of HIV among IDU populations and increasing rates of injecting in many countries calls for scaling up of NSPs as well as other harm reduction strategies.     

The Specific Endothelin A Receptor Antagonist ZD4054: Preclinical and Clinical Results

ContextZD4054 is a specific endothelin A (ET_A) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer (HRPC). ZD4054 binds specifically to the ET_A receptor, with no detectable activity at the ET_B receptor. In preclinical studies, ZD4054 inhibited endothelin (ET-1)-mediated changes in cellular invasiveness in vitro, and inhibited angiogenesis and growth of tumour xenografts in vivo. Consistent with its specific binding profile, ZD4054 inhibited ET_A-receptor-mediated antiapoptotic events while allowing ET_B-receptor-mediated proapoptotic signalling.Evidence acquisitionThe preclinical and clinical activity of ZD4054 is reviewed.Evidence synthesisIn the clinical setting, stable levels of circulating ET-1 following single ZD4054 doses up to 240 mg demonstrated the absence of ZD4054 activity at the ET_B receptor. ZD4054 is cleared principally via the urine, with a terminal elimination half-life of approximately 8–12 hours and with little accumulation after once-daily oral dosing.In a Phase 2 trial, patients with metastatic HRPC who were pain free or mildly symptomatic for pain were randomized to once-daily oral tablets of ZD4054 10 mg (n = 107), or 15 mg (n = 98), or matched placebo (n = 107). ZD4054 was generally well tolerated in this population, with an adverse effect profile consistent with its known pharmacological activity. The most common adverse effects were headache, peripheral oedema and nasal congestion. At the primary analysis there was no statistically significant difference in time to progression between the ZD4054-treated groups and placebo (hazard ratio [HR]: ZD4054 10 mg, 0.88 [80% CI 0.71, 1.09]; ZD4054 15 mg, 0.83 [0.66, 1.03]). However, a promising signal for prolonged overall survival was observed, which was sustained at a subsequent analysis (HR versus placebo: ZD4054 10 mg, 0.55 [80% CI 0.41, 0.73]; ZD4054 15 mg, 0.65 [0.49, 0.86]).ConclusionsThese results support the strategy of targeting the ET_A receptor in prostate cancer, and mandate further investigation of ZD4054 in Phase 3 clinical trials.     

Monotherapy with enoxaparin for the prevention of recurrent venous thromboembolism.

This study aimed to determine whether a weight-adjusted dose of subcutaneous enoxaparin is as effective and safe as oral acenocoumarol for the secondary prophylaxis of pulmonary embolism. Three hundred and eighty consecutive noncancer outpatients hospitalized with an episode of symptomatic pulmonary embolism selected treatment with acenocoumarol or enoxaparin at a dose of 1 mg/kg once daily after being informed of the type of administration and expected frequency of laboratory monitoring for both medicinal products. Endpoints were symptomatic recurrent thromboembolic events evaluated by standard objective testing, and a composite endpoint of recurrent venous thromboembolism, major bleeding, and death from any cause. One hundred and ninety-nine patients (52%) chose acenocoumarol therapy and 181 chose enoxaparin monotherapy. Four patients in the enoxaparin group (2.2%) and six patients in the acenocoumarol group (3%) had an objective thromboembolic recurrence (hazard ratio, 1.35; 95% confidence interval, 0.38-4.79; P = 0.64). Nine patients in the enoxaparin group (5.0%) had a hemorrhagic complication compared with 11 in the acenocoumarol group (5.5%) (P = 0.81). The hospital length of stay was shorter with enoxaparin compared with acenocoumarol (11 versus 16 days, P = 0.0001). Enoxaparin is as effective and safe as acenocoumarol in the secondary prevention of recurrent thromboembolic disease and is associated with shorter hospitalization.     

Physical symptoms/side effects during breast cancer treatment predict posttreatment distress

Background: Studies suggest that the period following completion of treatment can be distressing for cancer patients. One potentially important predictor of distress is physical symptoms/side effects during treatment.Purpose: A longitudinal, observational design was used to examine whether the number of physical symptoms/side effects experienced during treatment was a correlate of cancer-related distress and general distress 4 months after treatment completion, as measured by the Impact of Events Scale and the Mental Health subscale of the Short Form-36, respectively.Methods: Participants were 151 women who had completed chemotherapy and/or radiotherapy for ductal carcinoma in situ or stage 1 or 2 breast cancer. Hierarchical multiple regression was conducted with relevant sociodemographic, clinical, and psychiatric variables entered as controls.Results: Greater physical symptoms/side effects predicted greater total cancer-related distress, intrusive thoughts, and general distress. Physical symptoms/side effects did not significantly predict avoidance. Follow-up analyses indicated that the relationship between physical symptoms/side effects and general distress was mediated by both total cancer-related distress and intrusive thoughts.Conclusions: These results suggest that patients who experience greater physical symptoms/side effects during treatment are at greater risk for later cancer-related distress and, in turn, general distress. Future research should evaluate whether early intervention with these patients is effective in preventing or reducing distress in the posttreatment period. This work was supported by a grant from the National Cancer Institute (5R01 CA082822).     

Investigation of the negative chronotropic action of SK&F 86466 in the pithed normotensive rat

SK&F 86466, 6-chloro-3-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine, is a potent and selective antagonist of the α₂-adrenoceptor in vitro. This compound produced a small pressor response accompanied by a marked bradycardia when administered i.v. to the pithed normotensive rat. The pressor response was not affected by reserpine treatment, pretreatment with α- or β-adrenoceptor antagonists, atropine, or hexamethonium. The bradycardia was markedly reduced by bilateral vagotomy and pretreatment with atropine and attenuated by hexamethonium. The negative chronotropic action of SK&F 86466 was abolished by a combination of vagotomy and atropine. Mediation of the bradycardia by a baroreceptor reflex was ruled out by the observations that a lack of change in heart rate was associated with the vasopressor response to phenylephrine in the pithed rat pretreated with propranolol. It is concluded that the negative chronotropic action of SK&F 86466 in the pithed rat is mediated indirectly by activation of the cholinergic innervation of the heart.