Citations

Abstract Background: Activation of the PI3K pathway, by PIK3CA mutation or amplification or PTEN deletion, has been implicated in a wide variety of human cancers. PF-05212384 is a dual-specificity inhibitor of PI3K and mTOR that is formulated for intravenous (IV) administration. PF-05213384 is the first IV PI3K/mTOR inhibitor to be tested in a clinical trial. Methods: In this ongoing phase 1 trial, PF-05212384 was administered once weekly, using a modified continual reassessment method (CRM) for estimation of the maximum tolerated dose (MTD). Assessments included safety (NCI CTC AE v4.0), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (RECIST v1.1). PD assessments included blood glucose and immunohistochemistry analysis of phosphoprotein biomarkers in tumor and surrogate tissue (hair follicles). The population was actively enriched for patients with dysregulation in the PI3K pathway. Results: As of 15 March 2011, 47 patients have been enrolled at doses ranging from 10 mg to 319 mg. Median age was 58. Represented tumor types included CRC (8), NSCLC (4), ovarian/endometrial/cervical (8), salivary (3) and gastric/esophageal (3). Analysis of archived tumor biopsies revealed PI3K pathway alterations in 12/26 evaluable patients; alterations included PTEN loss, PIK3CA mutation or amplification. PF-05212384 was well tolerated with the most common AEs being mucositis (44%), nausea (42%), fatigue (28%), rash (28%), and hyperglycemia (26%). DLTs included mucositis, rash, transaminase elevation, and hyperglycemia. An MTD of 154 mg weekly has been estimated. PF-05212384 is eliminated with a half-life of approximately 16 hours, with low clearance (5–9 L/h) and relatively high volume of distribution (54–144 L). Changes in blood glucose have been observed in 13 patients, including 2 patients with Grade 3 hyperglycemia, a known effect of PI3K/Akt pathway suppression. No objective tumor response has been observed; 12 patients have achieved stable disease (SD) in excess of 16 weeks, with 9 patients on study for ≥24 weeks and one patient (salivary) on study for >46 weeks. Enrollment to MTD expansion cohorts is ongoing. Conclusions: Weekly administration of PF-05212384 is safe and tolerable across dose levels with multiple patients deriving clinical benefit with prolonged SD. The occurrence of hyperglycemia is suggestive of target modulation. Updated data for safety, PK, PD and antitumor activity will be presented Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A167.

Background —In patients receiving intracoronary stents, stent thrombosis is reduced when ticlopidine therapy is combined with aspirin after the procedure. However, ticlopidine causes neutropenia in 1% of patients when administered for >2 weeks, and little is known about the duration that ticlopidine needs be administered to prevent stent thrombosis. Methods and Results —We analyzed 827 patients undergoing successful stent placement in 1061 coronary segments at Mayo Clinic who were treated between May 1, 1996, and October 31, 1997. Chronic warfarin therapy, cardiogenic shock, and enrollment in research protocols requiring 4 weeks of ticlopidine were exclusion criteria; ticlopidine was discontinued after 14 days in all remaining patients. The mean age of the study population was 64±11 years; 49% had suffered a prior infarction, 20% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 31% of patients and suboptimal results from balloon angioplasty in 18%. Placement was elective in 51% of patients, and 10.3% of patients were treated within 12 hours of an acute myocardial infarction. Mean nominal stent size was 3.3±0.5 mm. High-pressure inflations (≥12 atm) were performed in all patients (mean, 17±4 atm). Intravascular ultrasound was used to facilitate stent placement in 8.8% of patients. Abciximab was administered to 38% of patients; 11% of patients who were at increased risk of stent thrombosis were treated with enoxaparin for 10 to 14 days. Adverse cardiovascular events in the 14 days after stent placement occurred in 11 patients (1.3%). Two patients died of nonischemic causes (sepsis and renal failure) in the 15th through 30th days after ticlopidine was stopped. However, there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures between the 15th and 30th days; stent thrombosis did not occur in any patient after ticlopidine had been stopped. No patient developed neutropenia, although 1.8% of the first 489 patients who were closely monitored for side effects from ticlopidine developed side effects requiring its discontinuation, and milder side effects occurred in 4.7%. Conclusions —In patients receiving intracoronary stents, the discontinuation of ticlopidine therapy 14 days after stent placement is associated with a very low frequency of stent thrombosis and other adverse events.

Background —This study applied the New York State conventional coronary angioplasty (PTCA) model of clinical outcomes to evaluate whether it has relevance in the current era of stent implantation. The model was developed in 62 670 patients treated with conventional PTCA from 1991 to 1994 to risk adjust mortality and bypass surgery after PTCA. Since then, stents have become the dominant form of intervention. Whether that model remains relevant is uncertain. Methods and Results —All patients undergoing stenting at the Mayo Clinic from 1995 to 1998 were analyzed for in-hospital mortality, bypass surgery performed after attempted stenting, and longer-term mortality. No patients were excluded. The New York model was used to risk adjust and predict in-hospital and follow-up mortality. There were 3761 patients with 4063 procedural admissions for stenting; 6472 target vessel segments were attempted, and 96.1% of procedures were successful. With the New York multivariable risk factor equation, 79 in-hospital deaths were expected (1.95%); 66 deaths (1.62%) were observed. The New York model risk score in a logistic regression model was the most significant factor associated with in-hospital mortality (OR, 1.86; P <0.001). During a mean follow-up of 1.2±1.0 years, there were 154 deaths. Multivariable analysis documented 6 factors associated with subsequent mortality; New York risk score was the most significant (χ 2 =16.64, P =0.0001). Conclusions —Although the New York mortality model was developed in an era of conventional angioplasty, it remains relevant in patients undergoing stenting. The risk score derived from that model is the variable most significantly associated with not only in-hospital but also longer-term outcome.

Background The use of exercise echocardiography for the diagnosis of coronary artery disease (CAD) has been validated in pilot studies but is not documented in clinical practice and in women comparatively with men. The objectives of this study were to determine the effects of sex and of test verification bias on the diagnostic performance of exercise echocardiography. Methods and Results Three thousand six hundred seventy-nine consecutive patients (1714 women, 1965 men) who underwent an exercise echocardiographic study were studied; the observed sensitivity, specificity, and correct classification rate were calculated among 340 patients (244 men, 96 women) who underwent angiography; to study the effect of test verification bias, sensitivity and specificity were estimated for all patients who underwent exercise echocardiography including those not referred to angiography. In the angiographic group, the prevalence of CAD was 60% in women and 80% in men. The observed sensitivity and specificity of exercise echocardiography was 78% and 44% in men and 79% and 37% in women. After adjustment for test verification bias, the estimated sensitivity was lower in women (32% versus 42% in men), whereas specificity was similar in both sexes. The positive predictive value was lower in women (66%) compared with men (84%). Conclusions In clinical practice, test verification bias results in a lower observed specificity and a higher sensitivity of exercise echocardiography. In women, positive predictive value and adjusted sensitivity are lower compared with that in men.

Background The endothelium modulates vascular tone through release of vasodilating substances, such as endothelium-derived relaxing factors, and vasoconstricting substances, such as endothelin. Endothelin concentrations are elevated in humans with atherosclerosis and in hypercholesterolemic pigs. Furthermore, the endothelium-dependent vasodilator acetylcholine increases endothelin in hypercholesterolemia in association with coronary vasoconstriction. The present study was designed to test the hypotheses that coronary endothelial dysfunction in humans is characterized by enhanced coronary and circulating endothelin and that the vasoconstriction associated with acetylcholine results in further release of coronary endothelin. Methods and Results Coronary and circulating endothelin concentrations were measured at baseline and during intracoronary acetylcholine administration in 20 patients undergoing diagnostic coronary angiography. Patients were divided into two groups on the basis of their response to intracoronary acetylcholine. Group 1 (n=7) demonstrated a normal vasodilatory response, but group 2 (n=13) demonstrated coronary vasoconstriction. Baseline coronary and circulating endothelin concentrations (as determined by coronary sinus and femoral artery measurements, respectively) were higher in patients who responded to acetylcholine with coronary vasoconstriction (group 2) than in group 1 patients (coronary sinus, 15.9±1.0 pg/mL versus 7.1±1.0 pg/mL; femoral, 14.1±0.9 pg/mL versus 6.8±1.0 pg/mL, respectively; P <.01). In response to intracoronary acetylcholine, a further increase in coronary endothelin was observed only in group 2; this increase correlated with changes in coronary artery diameter. Conclusions This study demonstrates that endothelin immunoreactivity is enhanced in the coronary and systemic circulation in humans with coronary endothelial dysfunction. Moreover, acetylcholine further increased coronary endothelin concentration in patients with coronary endothelial dysfunction and was associated with coronary vasoconstriction. These observations strongly support a role for endothelin as an early participant in and marker for coronary endothelial dysfunction in humans.

Background Women who undergo coronary angioplasty have a higher in-hospital mortality than men, although much of this difference can be accounted for by their poorer clinical characteristics at the time of their procedures. However, whether or not there are important long-term differences in outcome between women and men after coronary angioplasty is not clear. Methods and Results A retrospective analysis was performed of 3027 consecutive patients (824 women and 2203 men) who underwent successful angioplasty and who have been followed continuously for a mean of 5.5 years (range, 0.5 to 14 years). Follow-up is 100% complete. Event-free survival was assessed by the Kaplan-Meier method, and clinical end points were also examined by Cox proportional-hazards models to account for important baseline differences when appropriate. There was a trend toward lower survival among women during follow-up, but this was not significant ( P =.06). The relative risk of death among women compared with men after adjustment for baseline differences was 0.94 (CI, 0.76 to 1.15; P =NS). No significant sex differences in occurrence of Q-wave myocardial infarction were observed. Women were less likely to remain free of angina after 10 years (34% versus 37%, respectively; P =.008), but after adjustment for baseline differences, this difference was not significant (relative risk of angina, 1.07; CI, 0.95 to 1.21). Women tended to have less coronary artery bypass surgery performed during follow-up ( P =.06); adjusting for baseline differences made this difference more significant (relative risk, 0.79; CI, 0.64 to 0.96; P =.02). Among patients who were not treated in the setting of acute infarction, no sex differences in survival and freedom from myocardial infarction were noted. Conclusions After successful coronary angioplasty, the long-term prognosis for women is excellent and is similar to that observed in men. Risk-adjusted survival did not differ significantly between the sexes, but less frequent use of subsequent surgical revascularization was observed in women.

BACKGROUND Complete revascularization after coronary artery bypass surgery is a logical goal and improves symptomatic outcome and survival. However, the impact of complete revascularization in patients with three-vessel coronary disease with varying severities of angina and left ventricular dysfunction has not been clearly defined. METHODS AND RESULTS The study was performed as a retrospective analysis of 3,372 nonrandomized surgical patients from the Coronary Artery Surgery Study (CASS) Registry who had three-vessel coronary disease. Group 1 (894 patients) had class I or II angina (Canadian Cardiovascular Society criteria) and group 2 (2,478 patients) had class III or IV angina. In group 1, adjusted cumulative 4-year survivals according to the number of vessels bypassed were 85% (one vessel), 94% (two vessels), 96% (three vessels), and 96% (more than three vessels) (log rank, p = 0.022). Adjusted event-free survival (death, myocardial infarction, definite angina, or reoperation) was not influenced by the number of vessels bypassed, nor was the anginal status among patients remaining alive after 5 years. In group 2, adjusted cumulative 5-year survivals were 78% (one vessel), 85% (two vessels), 90% (three vessels), and 87% (more than three vessels) (log rank, p = 0.074). Adjusted event-free survivals after 6 years were 23% (one vessel), 23% (two vessels), 29% (three vessels), and 31% (more than three vessels) (p = 0.025); at 5 years, those with more complete revascularization were more likely to be asymptomatic or free of severe angina. Among group 2 patients with ejection fractions less than 0.35, 6-year survival was 69% for those with grafts to three or more vessels versus 45% for those with grafts to two vessels (p = 0.04). Placing grafts to three or more vessels was independently associated with improved survival and event-free survival in group 2 but not group 1 patients. The case-fatality rates among 529 patients experiencing a myocardial infarction during follow-up was significantly higher for patients with less complete revascularization. CONCLUSIONS Complete revascularization (grafts to three or more vessels) in patients with three-vessel coronary disease appears to most benefit those with severe angina and left ventricular dysfunction.