Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Although in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Relevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016. The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). RESULTS: A total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643). No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). CONCLUSION: Our pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.

Radiosurgery in the management of pediatric brain tumors.

A total of 114 patients with benign and malignant intracranial tumors were treated by Valentino at the Flaminia Radiosurgical Center using a Philips 6-MeV linear accelerator between 1987 and 1995. The tumor locations break down as follows: 36 in the cerebral hemispheres, 14 in the region of the hypothalamus/optic chiasm, 21 in the III ventricle/pineal region, 3 in the basal ganglia, 27 in the posterior fossa, 13 in the brain stem. Seventy-nine patients had multivariate/combined treatment consisting of surgery or biopsy followed by chemotherapy, radiotherapy and/or radiosurgery. Thirty-five were not operated on or biopsied but were treated primarily by radiosurgery, which was associated with chemotherapy and conventional radiotherapy. The short- and long-term results were evaluated separately for each pathology in an attempt to derive guidelines for future treatment. For tumors of the pineal region, we are of the opinion that radiosurgery is the treatment of choice in children and that more than one-third of patients can be cured by this means. The remaining patients require surgery and/or chemotherapy in addition. For medulloblastomas radiosurgery may be useful to control local recurrence if coupled with chemotherapy. In the case of ependymomas, partly because of the extreme malignancy of the lesions in our series, radiosurgery did not succeed in controlling local recurrence. We fear that limiting treatment to radiosurgery, rather than prescribing conventional radiotherapy when indicated, could permit CNS seeding. For craniopharyngiomas radiosurgery proved useful for controlling solid remnants. In glial tumors radiosurgery helped either to "sterilize" the tumor bed after removal or to treat remnants of the lesions in critical areas; for diffuse brain stem gliomas it should be considered the treatment of choice.

Proarrhythmic effects of pinacidil are partially mediated through enhancement of catecholamine release in isolated perfused guinea-pig hearts.

The contribution of adrenergic stimulation to the proarrhythmic effects of pinacidil (30 microM), an opener of ATP-sensitive potassium channels (K+ATP), was tested in an isolated guinea-pig heart model of global ischemia (10 min) and reperfusion (10 min). None (0%) of the control hearts (n=10) elicited arrhythmias during ischemia or reperfusion. In the pinacidil-treated group, one heart (5%) experienced episodes of ventricular tachycardia (VT)/fibrillation (VF) during normoxia. During ischemia, 63% (12 out of 19) of pinacidil-treated hearts exhibited episodes of VT or VF. Hearts not in VT or VF (n=7) at the time of reperfusion, exhibited 71% VT and 43% VT/VF upon reperfusion. Proarrhythmic effects of pinacidil during ischemia or reperfusion were completely reversed by glyburide (n=9; 10 microM), a K+ATP antagonist, or nadolol (n=9; 3 microM), a beta-adrenergic antagonist. Isoproterenol (n=10; 50 nM), a beta-adrenergic agonist, induced a 20% incidence of ischemic VT and VF, and a 70% incidence of reperfusion VF, while methoxamine (n=10; 10 microM), an alpha-adrenergic agonist, demonstrated little proarrhythmia (20% VT/VF at reperfusion only). Proarrhythmic effects of isoproterenol were reversed by nadolol, but not glyburide. Pinacidil caused a slight potentiation of tachycardia induced by a bolus injection of tyramine (30 micro g), an indirectly acting sympathomimetic, but bolus injections of pinacidil (100 micro g) had no effect on heart rate. Nisoxetine, a catecholamine uptake 1 inhibitor, had no proarrhythmic effects when given alone. Catecholamine levels were reduced in pinacidil-treated hearts relative to vehicle-treated. In conclusion, it is suggested that the proarrhythmic effects of pinacidil following global ischemia and reperfusion in the isolated perfused guinea-pig heart appears to involve stimulation of beta-adrenoceptors. These proarrhythmic effects of pinacidil do not appear to be mediated solely through direct opening of K+ATP, but rather through an indirect enhancement of catecholamine release.

Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection.

Previous studies showed a poor correlation between sarcolemmal K+ currents and cardioprotection for ATP-sensitive K+ channel (KATP) openers. Diazoxide is a weak cardiac sarcolemmal KATP opener, but it is a potent opener of mitochondrial KATP, making it a useful tool for determining the importance of this mitochondrial site. In reconstituted bovine heart KATP, diazoxide opened mitochondrial KATP with a K1/2 of 0.8 mumol/L while being 1000-fold less potent at opening sarcolemmal KATP. To compare cardioprotective potency, diazoxide or cromakalim was given to isolated rat hearts subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset of contracture with a similar potency (EC25, 11.0 and 8.8 mumol/L, respectively) and improved postischemic functional recovery in a glibenclamide (glyburide)-reversible manner. In addition, sodium 5-hydroxydecanoic acid completely abolished the protective effect of diazoxide. While-myocyte studies showed that diazoxide was significantly less potent than cromakalim in increasing sarcolemmal K+ currents. Diazoxide shortened ischemic action potential duration significantly less than cromakalim at equicardioprotective concentrations. We also determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac KATP activity. Cromakalim and diazoxide were both potent activators of K+ flux in this preparation (K1/2 values, 1.1 +/- 0.1 and 0.49 +/- 0.05 mumol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+ flux through the diazoxide-opened mitochondrial KATP. The profile of activity of diazoxide (and perhaps KATP openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial KATP.

Hemodynamic and cardiac effects of BMS-180448, a novel K+ATP opener, in anesthetized dogs and isolated rat hearts.

Hemodynamic and cardiac effects of BMS-180448 (0.3-10 mg/kg i.v.) or cromakalim (0.01-0.3 mg/kg i.v.) were evaluated in anesthetized open-chest dogs and isolated perfused rat hearts. In the canine studies, heart rate (HR), mean arterial pressure and left ventricular pressure were measured as well as electromagnetic blood flows recorded from the aortic, renal, coronary and femoral vascular beds. BMS-180448 was 187-fold less potent than cromakalim in lowering blood pressure (ED-20 values of 7.84, and 0.042 mg/kg for BMS-180448 and cromakalim, respectively). Both compounds increased HR. Effects of BMS-180448 occurred at doses higher than those of cromakalim, but at doses slightly lower than those needed to cause hypotension (ED(HR)/ED(MABP) ratio of 0.18 for BMS-180448). BMS-180448 had no effect on myocardial contractility or relaxation over the doses studied, whereas cromakalim significantly increased +dP/dt and lowered -dP/dt. Effects on +dP/dt were associated with a decrease in blood pressure. Although BMS-180448 reduced total peripheral resistance (ED-25 = 5.75 mg/kg), it had little effect on specific vascular beds, with the exception of the coronary bed. BMS-180448, unlike cromakalim which caused more general vasodilating effects, appeared to be relatively selective in dilating the coronary vascular bed. In isolated perfused rat hearts, BMS-180448, 10-fold more potent as a cardioprotectant (EC25 = 2.7 microM) than as a cardiodepressant (ED-25 = 27.8 microM), had no effect on HR, suggesting a lack of effect of BMS-180448 on myocardial conduction. In conclusion, BMS-180448, a recently developed K+ATP opener, exerted less hypotensive and more selective vascular effects than did cromakalim. These results suggest that BMS-180448, at doses previously reported to give cardioprotection, should have a safe hemodynamic profile.

Glyburide-reversible cardioprotective effect of BMS-180448 is independent of action potential shortening.

OBJECTIVE: We determine if action potential duration (APD) shortening and cardioprotection are separable phenomena in ATP-sensitive potassium channel (KATP) openers which protect ischemic myocardium via a glyburide-reversible mechanism. METHODS: We determined the effect of the weakly vasodilating KATP opener, BMS-180448, and the less cardiac-selective cromakalim, on APD in normal, hypoxic or ischemic guinea pig papillary muscles or isolated hearts and compared their APD effects with their cardioprotective activity in isolated guinea pig hearts. RESULTS: In isolated ischemic guinea pig hearts, cromakalim and BMS-180448 had similar cardioprotective potencies (EC25 of 3.2 and 3.3 microM, respectively, for increasing time to the onset of contracture). At 10 microM, BMS-180448 produced no APD shortening, yet was equally protective at this concentration compared to cromakalim, which produced profound APD shortening under either hypoxic or ischemic conditions. The cardioprotective effects of both compounds at 10 microM were abolished by 0.3 microM glyburide. CONCLUSIONS: APD shortening is not correlated with cardioprotective activity for BMS-180448 and cromakalim while their cardioprotective effects are abolished by glyburide. These results suggest the possibility of reduced proarrhythmic activity in some KATP openers and that their cardioprotective activity is not associated with sarcolemmal KATP opening.

Effects of cromakalim or glibenclamide on arrhythmias and dispersion of refractoriness in chronically infarcted in anesthetized dogs.

The proarrhythmic effects of the ATP-sensitive potassium channel modulators cromakalim (n = 10; 0.01 to 0.3 mg/kg i.v.), glibenclamide (n = 10; 0.3 to 10 mg/kg i.v.) or volume equivalents of vehicle (n = 10) were evaluated in post-infarcted anaesthetised dogs. Dogs were anaesthetised, subjected to an anterior-apical myocardial infarction, and allowed to recover. At 7.4 +/- 0.7 days post infarction, animals were anaesthetised again, electrophysiologic measurements (effective refractory periods, QT-intervals and ventricular fibrillation thresholds) were taken, and animals were tested for arrhythmias using a programmed electrical stimulation protocol. Only animals that did not have programmed electrical stimulation-inducible arrhythmias were used. Ventricular fibrillation thresholds were determined twice, once before the first dose then after the last dose of drug. At the end of the experiment, animals were subjected to ligation of the left circumflex coronary artery and survival was measured over the next two hours. Cromakalim significantly increased heart rate and decreased blood pressure. Although cromakalim significantly reduced effective refractory periods, it neither increased electrical dispersion, as determined by the standard deviation or coefficient of variance of the effective refractory period, nor did it enhance inducibility (0 out of 10 in both vehicle and cromakalim treated animals), change ventricular fibrillation thresholds, or reduce sudden death survival relative to vehicle. Glibenclamide did not increase electrical dispersion, but slightly increased the incidence of programmed electrical stimulation-induced arrhythmias (3 out of 10), and lowered ventricular fibrillation thresholds values. However, these changes were not statistically significant. Glibenclamide did not significantly affect survival relative to vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardioprotection with the KATP opener cromakalim is not correlated with ischemic myocardial action potential duration.

We endeavored to determine if the enhanced shortening of the myocardial action potential duration (APD) during ischemia can be dissociated from the cardioprotective effects of the adenosine triphosphate (ATP) sensitive potassium channel (KATP) opener cromakalim. To establish if there is a relationship between APD shortening and the cardioprotective effect of cromakalim, we determined the effect of a dose of the delayed rectifier (IKr) blocker dofetilide (which abolishes the APD shortening effect of cromakalim) on the cardioprotective activity of cromakalim. Cromakalim was infused at a previously determined cardioprotective dose (10 micrograms/kg + 0.3 micrograms/kg/min infusion i.c.), and we determined the effect of 1 mg/kg (followed by a 0.01 mg/kg/min i.v. infusion) dofetilide alone and in combination with cromakalim on APD shortening and infarct size (90-min coronary occlusion and 5-h reperfusion) in anesthetized dogs. Dofetilide completely abolished the APD shortening effects of cromakalim during ischemia such that APD was similar to preischemic values. Cromakalim only shortened the APD during ischemia, although this effect was attenuated late into ischemia. Cromakalim significantly reduced infarct size (40% reduction from vehicle group value), whereas dofetilide alone had no effect. Dofetilide, at a dose that prevented the cromakalim-induced shortening of APD in ischemic tissue, did not attenuate the cardioprotective effects of cromakalim. No differences in collateral blood flow for any of the groups were observed. Dofetilide did cause a slight bradycardia, but this effect is unlikely to affect the interpretation of the results. These data suggest that APD shortening observed with the KATP opener cromakalim is not correlated with its cardioprotective effects.

Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448.

ATP-sensitive potassium channel (KATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference KATP openers (e.g., cromakalim, pinacidil) are potent relaxants of smooth muscle, their utility for treating myocardial ischemia may be limited by hypotension. Efforts aimed at development of a cardioprotective KATP opener with less vasorelaxant activity led to identification of the arylcyanoguanidine analogue BMS-180448. In globally ischemic rat hearts, BMS-180448 was cardioprotective (EC25 for increasing time to contracture = 2.5 microM), with potency equal to that of cromakalim (EC25 = 4.9 microM) despite being significantly less potent as a peripheral smooth muscle relaxant (methoxamine-constricted rat aorta). The cardioprotective effects of BMS-180448 in isolated perfused rat heart were abolished by the KATP blockers glyburide and sodium 5-hydroxydecanoate, indicating KATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single KATP opening by BMS-180448 in guinea pig cardiac myocytes. In anesthetized dogs, cromakalim was > 100-fold more potent than BMS-180448 in decreasing blood pressure (BP). In anesthetized dogs subjected to 90-min coronary occlusion/reperfusion, BMS-180448 reduced infarct size (IS) by 50% without hemodynamic effects. BMS-180448 provides the opportunity to explore the cardioprotective actions of this class of agents without the possible complications (hypotension, coronary steal) that may be caused by the currently available KATP openers.