Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is crucial to many aspects of cell growth, survival and apoptosis, and its constitutive activation has been implicated in the both the pathogenesis and the progression of a wide variety of neoplasias. Hence, this pathway is an attractive target for the development of novel anticancer strategies. Recent studies showed that PI3K/Akt signaling is frequently activated in acute myeloid leukemia (AML) patient blasts and strongly contributes to proliferation, survival and drug resistance of these cells. Upregulation of the PI3K/Akt network in AML may be due to several reasons, including FLT3, Ras or c-Kit mutations. Small molecules designed to selectively target key components of this signal transduction cascade induce apoptosis and/or markedly increase conventional drug sensitivity of AML blasts in vitro. Thus, inhibitory molecules are currently being developed for clinical use either as single agents or in combination with conventional therapies. However, the PI3K/Akt pathway is important for many physiological cellular functions and, in particular, for insulin signaling, so that its blockade in vivo might cause severe systemic side effects. In this review, we summarize the existing knowledge about PI3K/Akt signaling in AML cells and we examine the rationale for targeting this fundamental signal transduction network by means of selective pharmacological inhibitors

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is crucial to many aspects of cell growth, survival and apoptosis, and its constitutive activation has been implicated in the both the pathogenesis and the progression of a wide variety of neoplasias. Hence, this pathway is an attractive target for the development of novel anticancer strategies. Recent studies showed that PI3K/Akt signaling is frequently activated in acute myeloid leukemia (AML) patient blasts and strongly contributes to proliferation, survival and drug resistance of these cells. Upregulation of the PI3K/Akt network in AML may be due to several reasons, including FLT3, Ras or c-Kit mutations. Small molecules designed to selectively target key components of this signal transduction cascade induce apoptosis and/or markedly increase conventional drug sensitivity of AML blasts in vitro. Thus, inhibitory molecules are currently being developed for clinical use either as single agents or in combination with conventional therapies. However, the PI3K/Akt pathway is important for many physiological cellular functions and, in particular, for insulin signaling, so that its blockade in vivo might cause severe systemic side effects. In this review, we summarize the existing knowledge about PI3K/Akt signaling in AML cells and we examine the rationale for targeting this fundamental signal transduction network by means of selective pharmacological inhibitors

The sirolimus-eluting Cypher Select coronary stent for the treatment of bare-metal and drug-eluting stent restenosis: insights from the e-SELECT (Multicenter Post-Market Surveillance) registry.

OBJECTIVES: This study sought to compare the 1-year safety and efficacy of Cypher Select or Cypher Select Plus (Cordis Corporation, Bridgewater, New Jersey) sirolimus-eluting stents (SES) with the treatment of bare-metal stents (BMS) and drug-eluting stent (DES) in-stent restenosis (ISR) in nonselected, real-world patients. BACKGROUND: There is paucity of consistent data on DES for the treatment of ISR, especially, DES ISR. METHODS: The e-SELECT (Multicenter Post-Market Surveillance) registry is a Web-based, multicenter and international registry encompassing virtually all subsets of patients and lesions treated with at least 1 SES during the period from 2006 to 2008. We enrolled in this pre-specified subanalysis all patients with at least 1 clinically relevant BMS or DES ISR treated with SES. Primary endpoint was major adverse cardiac events and stent thrombosis rate at 1 year. RESULTS: Of 15,147 patients enrolled, 1,590 (10.5%) presented at least 1 ISR (BMS group, n = 1,235, DES group, n = 355). Patients with DES ISR had higher incidence of diabetes (39.4% vs. 26.9%, p < 0.001), renal insufficiency (5.8% vs. 2.3%, p = 0.003), and prior coronary artery bypass graft (20.5% vs. 11.8%, p < 0.001). At 1 year, death (1.4% for BMS vs. 2.1% for DES, p = 0.3) and myocardial infarction (2.4% for BMS and 3.3% for DES, p = 0.3) rates were similar, whereas ischemia-driven target lesion revascularization and definite/probable late stent thrombosis were higher in patients with DES ISR (6.9% vs. 3.1%, p = 0.003, and 1.8% vs. 0.5%, p = 0.04, respectively). CONCLUSIONS: Use of SES for either BMS or DES ISR treatment is safe and associated with low target lesion revascularization recurrence and no apparent safety concern

Drug eluting stent implantation in patients requiring concomitant vitamin K antagonist therapy. One-year outcome of the worldwide e-SELECT registry.

BACKGROUND: Outcome of sirolimus-eluting stent (SES) in patients treated with an antivitamin K (VKA) agent before the PCI procedure is unknown. METHODS: A total of 7651 patients were selected among 15,147 recipients of SES, included in the worldwide e-SELECT registry, only from those centers which included at least one patient requiring VKA: 296 were pretreated with a VKA agent (VKA group), whereas 7355 patients from the same enrolling medical centers were not (NON-VKA group). The rates of 1) major adverse cardiac events (MACE), including all-cause deaths, myocardial infarction (MI) and target lesion revascularization, 2) stent thrombosis (ST) and 3) major bleeding (MB) in the 2 study groups were compared at 1, 6 and 12 months. RESULTS: The patients in VKA group were on average older as compared to those in NON-VKA group (67.7 ± 9.9 vs.62.9 ± 10.7, P&lt;0.001). The indications for pre-procedural anticoagulation were atrial fibrillation in 177 (59.8%), presence of a prosthetic valve in 21 (7.1%), embolization of cardiac origin in 17 (5.7%), pulmonary embolism or deep vein thrombosis in 17 (5.7%), and miscellaneous diagnoses in 64 (21.6%) patients. At 1 year, the rates of MACE and MB were higher in the VKA vs. the NON-VKA group (8.3% and 3% vs. 5.3% and 1.2%, P&lt;0.04 and P&lt;0.002, respectively). The 1-year rates of definite and probable ST were remarkably low in both groups (0.38% vs. 1.1%, p=0.4). CONCLUSIONS: Selected patients anticoagulated with VKA agent may safely undergo SES implantation. Those patients may receive a variety of APT regimen at the cost of a moderate increased risk of MB

Courier Gazette : Thursday, October 23, 1941

AIMS: Performing percutaneous coronary intervention (PCI) to multiple coronary lesions during the same procedure has potential economic and social advantages. However comprehensive outcome data of real world practice in a large population is limited. We aimed to compare short- and long-term outcomes between patients with multivessel coronary artery disease who either underwent single- or multivessel PCI within the e-SELECT registry. METHODS AND RESULTS: The e-SELECT registry combines data collected at 320 medical centres in 56 countries where patients received CYPHER Select® or CYPHER Select® Plus sirolimus-eluting stent (SES). Rates of myocardial infarction and major adverse cardiac event (MACE) (defined as any death, myocardial infarction or target lesion revascularisation) were compared between patients undergoing single-vessel versus multivessel PCI. A total of 15,147 patients who satisfied the inclusion criteria were included in the e-SELECT registry. Two thousand two hundred and seventy-eight (2,278) subjects (15%) underwent multivessel PCI and 12,869 (85%) had single-vessel PCI. The mean age was higher in the multivessel PCI group (63 vs. 62 years, p<0.001) and there was a higher prevalence of diabetes mellitus (32.4 vs. 30.0%, p=0.02). Lesions were more complex in the single-PCI group while pre- and post-dilatation were less common in the multivessel PCI group. Myocardial infarction within the first 30 days post PCI was more common in the multivessel PCI group (1.9 vs. 0.8%, p<0.001) and most of the infarctions were periprocedural (1.3 vs. 0.6%, p=0.001). Mortality and myocardial infarction at one-year were higher in the multivessel PCI group resulting in a significantly higher MACE (6.1 vs. 4.6%, p=0.005). CONCLUSIONS: Overall procedural and one year outcomes were excellent for both single- and multivessel procedures. However despite lower lesion complexity, performing multivessel PCI was associated with higher rates of periprocedural myocardial infarction and MACE when compared to single-vessel PCI in the e-SELECT registry