Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer.

BACKGROUND: Testing for EGFR mutations and ALK rearrangement has become standard in managing advanced nonsmall-cell lung cancer (NSCLC). However, many institutions in Europe, North America and other world regions continue to face a common challenge of facilitating timely molecular testing with rapid result turnaround time. We assessed the prevalence of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. METHODS: We conducted a retrospective chart review of a random sample of one-quarter of all patients with advanced NSCLC referred to the Princess Margaret Cancer Centre from 1 April 2010 to 31 March 2013. RESULTS: Of 300 patients reviewed, 175 seen by medical oncology had nonsquamous NSCLC, 72% of whom had biomarker testing carried out. Patients tested for biomarkers were more likely to be female (47% versus 21%, P = 0.002), Asian (27% versus 6%, P = 0.005) and never smokers (42% versus 8%, P < 0.0001). Only 21% of patients with biomarker testing had results available at their initial oncology consultation. This group had a shorter median time from consultation to treatment decision (0 versus 22 days, P = 0.0008) and time to treatment start (16 versus 29, P = 0.004). Thirteen percent underwent repeat biopsy for molecular testing after the initial consultation. Of those with positive EGFR or ALK results, 19% started chemotherapy before biomarker results became available. CONCLUSIONS: Awaiting biomarker testing results can delay treatment decisions and treatment initiation for patients with advanced NSCLC. This may be avoided by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens to ensure they are sufficient for molecular testing.

Epithelial ovarian cancer: role of pegylated liposomal Doxorubicin in prolonging the platinum-free interval and cancer antigen 125 trends during treatment.

BACKGROUND: Epithelial ovarian cancer's response to platinum retreatment depends on the duration of response to first-line platinum therapy. Platinum-free interval predicts subsequent platinum sensitivity and is a prognostic factor. Little has been published on the effect of pegylated liposomal doxorubicin (PLD) in the prolongation of treatment-free interval. METHODS: Patients treated with PLD were reviewed to assess response to platinum retreatment after PLD and to establish the use of cancer antigen 125 (Ca125) trends. All patients treated with PLD had progressed within 12 months of prior platinum therapy. Cancer antigen 125 fluctuations were categorized as the variances from the baseline (+/-10%, +/-10%-25%, and >25%). The response to chemotherapy was defined as Ca125 reduction from the baseline of more than 50%, clinical, or radiological response. RESULTS: Fifty-nine women were identified. The response rate (RR) to PLD was 28.9%, and the median overall survival from PLD initiation was 62 weeks. The number of women demonstrating more than 25% reduction in Ca125 from the baseline increased progressively with each cycle; at cycle 2, 11%; cycle 3, 18%; cycle 4, 22%; and cycle 5, 27% (trend significant between cycles 2 and 4, P = 0.004). Fifteen patients were re-treated with platinum after progression after PLD with 80% (12/15) of the patients responding. The RR to platinum retreatment after PLD compares favorably with the historical data on the response to second-line platinum retreatment. CONCLUSIONS: The sole use of early Ca125 trends in PLD treatment before cycle 4 may result in an erroneous discontinuation of PLD in potential responders. Retreatment with platinum after PLD may yield a good RR in selected patients even those with disease progression within 12 months after prior platinum treatment.

Selective axillary node sampling and radiotherapy to the axilla in the management of breast cancer.

AIMS: Axillary treatment for patients with early-stage breast cancer can be associated with considerable morbidity. Techniques, such as axillary node sampling (ANS) and, more recently, sentinel node biopsy, in combination with radiotherapy have the potential to reduce toxicity. A retrospective review of axillary treatment in patients with early-stage breast cancer treated at our institution between 1997 and 2003 was carried out to assess the outcome and morbidity of ANS in combination with radiotherapy. MATERIALS AND METHODS: The treatment policy was to carry out four-node, Edinburgh-style ANS except in those cases with either palpably enlarged nodes or cytological confirmation of involvement or with clinically obvious node involvement at surgery when level 2 axillary node clearance (ANC) was carried out. Patients with involved nodes after ANS received postoperative axillary radiotherapy. RESULTS: In total, 381 patients were included, 331 received ANS and 50 received ANC. The median follow-up was 6.5 years and overall survival at 5 years was 84%. Pathologically involved nodes were found in 152/331 (50%) ANS patients and 43/50 (86%) ANC patients. The rate of local recurrence (breast or chest wall) at 5 years was 4% (95% confidence interval 1-17%) in the ANC group and 2% (95% confidence interval 1-4%) in the ANS group. The nodal recurrence rate of those undergoing ANS was 3% (11/331) compared with 6% (3/50) for those treated by ANC. The rate of clinically significant lymphoedema at 5 years was significantly higher (P=0.01) in the ANC arm: 18% (95% confidence interval 9-32%) compared with 5% (95% confidence interval 3-8%) in those treated by ANS. Thirty-one cases received additional supraclavicular fossa irradiation because of the involvement of more than four nodes on ANS, which may not have been available with sentinel node biopsy and has implications for current practice. CONCLUSIONS: Selective ANS with the removal of a minimum of four nodes guides optimal locoregional treatment with good local control rates, low overall morbidity and may obviate the need for a second surgical procedure.

Antiplatelet therapy following drug-eluting stent implantation: new clinical data and recommendations.

Technological developments in percutaneous coronary interventions (PCI) allow the possibility for less invasive revascularization in an increasing number of patients with atherosclerotic coronary artery disease. Bare-metal stents (BMS) have considerably improved the efficacy of PCI in addition to greatly reducing restenosis. However, even with standard stents, restenosis has remained a significant limitation of this revascularization technique. The advent of drug-eluting stents (DES) has dramatically reduced in-stent restenosis and, as a result, the need for repeat revascularization. However, their potential thrombogenicity has raised concerns about their clinical utility and long-term safety. Indeed, there is a possible higher rate of late stent thrombosis (LST) with DES compared with BMS. Antiplatelet therapy has been shown to be efficient in preventing DES thrombosis. Nevertheless, in the future, significant improvement will occur to improve the safety and efficacy of this therapy. This article will summarize the pathophysiology and the epidemiology of stent thrombosis (ST). Definitions of definite, probable and possible ST will be described. Furthermore, clinical risk factors for ST will be clearly enumerated. Then, the various antiplatelet therapeutic strategies used to prevent ST will be taken in consideration. Finally, a summary of the major recommendations about antiplatelet therapy made by some of the most prestigious learned societies will be presented.

Molybdenum target specifications for cyclotron production of 99mTc based on patient dose estimates.

In response to the recognized fragility of reactor-produced (99)Mo supply, direct production of (99m)Tc via (100)Mo(p,2n)(99m)Tc reaction using medical cyclotrons has been investigated. However, due to the existence of other Molybdenum (Mo) isotopes in the target, in parallel with (99m)Tc, other technetium (Tc) radioactive isotopes (impurities) will be produced. They will be incorporated into the labeled radiopharmaceuticals and result in increased patient dose. The isotopic composition of the target and beam energy are main factors that determine production of impurities, thus also dose increases. Therefore, they both must be considered when selecting targets for clinical (99m)Tc production. Although for any given Mo target, the patient dose can be predicted based on complicated calculations of production yields for each Tc radioisotope, it would be very difficult to reverse these calculations to specify target composition based on dosimetry considerations. In this article, a relationship between patient dosimetry and Mo target composition is studied. A simple and easy algorithm for dose estimation, based solely on the knowledge of target composition and beam energy, is described. Using this algorithm, the patient dose increase due to every Mo isotope that could be present in the target is estimated. Most importantly, a technique to determine Mo target composition thresholds that would meet any given dosimetry requirement is proposed.

Imaging study of using radiopharmaceuticals labeled with cyclotron-produced 99mTc.

Cyclotron-produced 99mTc (CPTc) has been recognized as an attractive and practical substitution of reactor/generator based 99mTc. However, the small amount of 92-98Mo in the irradiation of enriched 100Mo could lead to the production of other radioactive technetium isotopes (Tc-impurities) which cannot be chemically separated. Thus, these impurities could contribute to patient dose and affect image quality. The potential radiation dose caused by these Tc-impurities produced using different targets, irradiation conditions, and corresponding to different injection times have been investigated, leading us to create dose-based limits of these parameters for producing clinically acceptable CPTc. However, image quality has been not considered. The aim of the present work is to provide a comprehensive and quantitative analysis of image quality for CPTc. The impact of Tc-impurities in CPTc on image resolution, background noise, and contrast is investigated by performing both Monte-Carlo simulations and phantom experiments. Various targets, irradiation, and acquisition conditions are employed for investigating the image-based limits of CPTc production parameters. Additionally, the relationship between patient dose and image quality of CPTc samples is studied. Only those samples which meet both dose- and image-based limits should be accepted in future clinical studies.

Recombinant soluble p-selectin glycoprotein ligand-1-Ig reduces restenosis through inhibition of platelet-neutrophil adhesion after double angioplasty in swine.

BACKGROUND: P-selectin mediates leukocyte recruitment to activated platelets and endothelium through its high-affinity receptor P-selectin glycoprotein ligand-1 (PSGL-1). Platelet and leukocyte activation and binding have been reported after coronary angioplasty and were correlated with restenosis. We investigated the effect of a recombinant soluble PSGL-1 (rPSGL-Ig) on the adhesion of platelets and neutrophils and the development of restenosis after double arterial injury. METHODS AND RESULTS: Four weeks after angioplasty of both carotid arteries in pigs, a second angioplasty was performed at the same sites, 15 minutes after a single administration of vehicle or rPSGL-1 (1 mg/kg IV). Animals were euthanized 1 hour, 4 hours, 1 week, or 4 weeks later. Adhesion of autologous (51)Cr-platelets and (111)In-neutrophils was quantified and histological/morphometric analyses were performed. Although rPSGL-Ig did not affect adherence of these cells 1 hour after injury, it significantly reduced the adhesion of platelets (50% at 4 hours and 85% at 1 week) and neutrophils (50% at 4 hours and 78% at 1 week) to deeply injured arteries. At 4 weeks, the residual lumen was 63% larger in rPSGL-Ig-treated arteries as compared with control arteries (6.1+/-0.6 versus 3.8+/-0.1 mm(2); P:<0.002). The neointimal area was slightly reduced (0.5 in rPSGL-Ig versus 0.7 mm(2) in control). The ratio of the external elastic lamina of injured to uninjured reference segments was >1 in treated arteries and <1 in control arteries. CONCLUSIONS: P-selectin antagonism with rPSGL-Ig inhibits early platelet/leukocyte adhesion on injured arteries and reduces restenosis through a positive impact on vascular remodeling. Hence, rPSGL-Ig may have potential in the prevention of restenosis.

Randomized trial comparing intravenous nitroglycerin and heparin for treatment of unstable angina secondary to restenosis after coronary artery angioplasty.

BACKGROUND: The treatment of unstable angina targets the specific pathophysiological thrombotic process at the site of the active culprit lesion. In unstable angina due to a restenotic lesion, smooth muscle cell proliferation and increased vasoreactivity may play a more important role than thrombus formation. Therefore, the relative benefits of nitroglycerin and heparin might differ in unstable angina associated with restenosis compared with classic unstable angina. METHODS AND RESULTS: We randomized 200 patients hospitalized for unstable angina within 6 months after angioplasty (excluding those with intracoronary stents) to double-blind administration of intravenous nitroglycerin, heparin, their combination, or placebo for 63+/-30 hours. Recurrent angina occurred in 75% of patients in the placebo and heparin-alone groups, compared with 42.6% of patients in the nitroglycerin-alone group and 41.7% of patients in the nitroglycerin-plus-heparin group (P<0.003). Refractory angina requiring angiography occurred in 22.9%, 29.2%, 4. 3%, and 4.2% of patients, respectively (P<0.002). The odds ratios for being event free were 0.24 (95% CI, -0.13 to 0.45, P=0.0001) for nitroglycerin versus no nitroglycerin and 0.98 (95% CI, -0.55 to 1. 73, P=NS) for heparin versus no heparin. No patient died or suffered myocardial infarction. CONCLUSIONS: Intravenous nitroglycerin is highly effective in preventing adverse ischemic events (recurrent or refractory angina) in patients with unstable angina secondary to restenosis, whereas heparin has no effect.

Local delivery of 17-beta-estradiol decreases neointimal hyperplasia after coronary angioplasty in a porcine model.

BACKGROUND: Neointimal hyperplasia is an important mechanism of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Systemically administered estrogen is known to inhibit neointimal formation after arterial injury. OBJECTIVES: We sought to assess the efficacy of locally delivered 17-beta-estradiol (BE) in inhibiting neointimal hyperplasia after PTCA. METHODS: Eighteen juvenile farm pigs were studied. Coronary angioplasty was performed in all three coronary arteries of each animal. After PTCA, each coronary artery in each pig was randomized to receive either local delivery of 600 microg BE, vehicle alone or PTCA only. Twelve animals were euthanized at 28 days for morphometric analysis, and four animals were euthanized at seven days for immunohistochemical analysis of vascular smooth muscle cell (SMC) proliferative activity. Two animals died a few days after PTCA and were excluded. RESULTS: On morphometric study, the arterial segments treated with BE demonstrated significantly less neointimal proliferation. Arteries treated with BE had reductions in several indexes of restenosis compared with arteries treated with vehicle alone or PTCA only: neointimal area (0.4+/-0.09 mm2 for BE vs. 1.14+/-0.33 mm2 for vehicle alone vs. 0.88+/-0.2 mm2 for PTCA only, p<0.05), percent neointima (12.16+/-2.57% vs. 25.46+/-4.73% vs. 23.02+/-3.97%, p<0.025), neointima/media area (0.59+/-0.14 vs. 1.75+/-0.41 vs. 1.67+/-0.43, p<0.01) and restenotic index (1.3+/-0.14 vs. 2.42+/-0.22 vs. 2.4+/-0.23, p<0.005). Immunohistochemistry showed decreased SMC proliferative activity in BE-treated arteries compared with the other two treatment groups (p<0.05). CONCLUSIONS: Local delivery of BE significantly decreases neointimal hyperplasia after PTCA in pigs, probably by the inhibition of SMC proliferation.

Platelets and restenosis.

Restenosis is currently the major limitation of percutaneous transluminal coronary angioplasty (PTCA). Factors such as elastic recoil, migration of vascular smooth muscle cells from media to intima, neointimal proliferation and vascular remodeling underly the restenotic process. Presently there is no effective therapy available for restenosis. The role of platelets in the development of thrombosis and abrupt closure after PTCA is well recognized. However, the effects of platelets in PTCA extend well beyond the early phase. Although antiplatelet agents such as glycoprotein IIb/IIIa antagonists have been reported to reduce target vessel revascularization, major unresolved controversies still exist. This report reviews the potential role of platelets in restenosis. Various drugs, successfully tested in experimental studies and in a small number of human studies, that inhibit the effect of platelets on the restenotic process are also reviewed.

Coronary artery endothelial protection after local delivery of 17beta-estradiol during balloon angioplasty in a porcine model: a potential new pharmacologic approach to improve endothelial function.

OBJECTIVES: The goal of this research was to study the effect of locally delivered 17beta-estradiol (17beta-E) during angioplasty on endothelial function after percutaneous transluminal coronary angioplasty (PTCA) at four weeks. BACKGROUND: The endothelium plays a major role in the structural and functional integrity of coronary arteries and is damaged by PTCA. METHODS: Juvenile swine were subjected to PTCA, after which each artery was randomly-assigned to 600-microg 17beta-E delivered locally, an equal volume of vehicle (V) or PTCA alone. After four weeks, the improvement in endothelial function was assessed by angiography using intracoronary acetylcholine (Ach) infusion and by immunohistochemistry. RESULTS: At 10(-5) mol/l and 10(-4) mol/l Ach, significant vasoconstriction was noted in arteries treated with PTCA alone (p < 0.01 and p < 0.0001, respectively) and with PTCA plus V (p < 0.02 and p < 0.001, respectively). No significant vasoconstrictive response to Ach was observed in arteries treated with PTCA plus 17beta-E. Immunohistochemistry of vessels four weeks after PTCA revealed enhanced re-endothelialization (p < 0.0005) and endothelial nitric-oxide synthase (eNOS) expression (p < 0.0005) in PTCA plus 17beta-E-treated arteries compared with the other two treatment groups. Arteries treated with 17beta-E showed significantly lower neointima formation, which correlated inversely with the extent of re-endothelialization and eNOS expression. CONCLUSIONS: Locally delivered 17beta-E significantly enhances re-endothelialization and endothelial function after PTCA, possibly by improving the expression of eNOS. Since endothelial dysfunction can promote both restenosis and coronary spasm, local 17beta-E administration is a promising new approach to improve long-term results after PTCA.

Management of coronary artery disease: therapeutic options in patients with diabetes.

OBJECTIVES: The aim of this review is to discuss the particularities of coronary artery disease (CAD), the effect of intensive medical management and the outcome of percutaneous and surgical revascularization in patients with diabetes mellitus (DM). BACKGROUND: CAD represents the leading cause of death in patients with DM. Numerous clinical, biological and angiographic risk factors have been shown to be associated with CAD in diabetic patients. METHODS: Metabolic abnormalities in patients with DM including insulin resistance, hyperglycemia and dyslipidemia are briefly discussed. Then the potential roles of medical management and of percutaneous and surgical coronary revascularization are more extensively reviewed. RESULTS: More vigorous control of hyperglycemia, hyperlipidemia, hypertension and other risk factors may be of crucial importance for risk reduction. Despite remarkable progress in recent years, the choice of a coronary revascularization strategy remains a challenge in these patients. Diabetic patients with CAD are predisposed to higher cardiovascular events after balloon angioplasty. Whether stenting and new antiplatelet drugs improve the results of percutaneous revascularization in this population needs further evaluation. The superiority of the surgical approach is also not definitely established. Therefore, many aspects of coronary revascularization are still unclear in these patients. CONCLUSIONS: The results of ongoing randomized trials comparing multiple coronary stents to bypass surgery will likely provide some answers to our questions and additional randomized trials evaluating intensive diabetic control with or without coronary revascularization are needed to determine the best therapeutic approach in these patients.

Quantitative analysis of relationships between irradiation parameters and the reproducibility of cyclotron-produced (99m)Tc yields.

Cyclotron production of (99m)Tc through the (100)Mo(p,2n) (99m)Tc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. An exciting aspect of this approach is that it can be implemented using currently-existing cyclotron infrastructure to supplement, or potentially replace, conventional (99m)Tc production methods that are based on aging and increasingly unreliable nuclear reactors. Successful implementation will require consistent production of large quantities of high-radionuclidic-purity (99m)Tc. However, variations in proton beam currents and the thickness and isotopic composition of enriched (100)Mo targets, in addition to other irradiation parameters, may degrade reproducibility of both radionuclidic purity and absolute (99m)Tc yields. The purpose of this article is to present a method for quantifying relationships between random variations in production parameters, including (100)Mo target thicknesses and proton beam currents, and reproducibility of absolute (99m)Tc yields (defined as the end of bombardment (EOB) (99m)Tc activity). Using the concepts of linear error propagation and the theory of stochastic point processes, we derive a mathematical expression that quantifies the influence of variations in various irradiation parameters on yield reproducibility, quantified in terms of the coefficient of variation of the EOB (99m)Tc activity. The utility of the developed formalism is demonstrated with an example. We show that achieving less than 20% variability in (99m)Tc yields will require highly-reproducible target thicknesses and proton currents. These results are related to the service rate which is defined as the percentage of (99m)Tc production runs that meet the minimum daily requirement of one (or many) nuclear medicine departments. For example, we show that achieving service rates of 84.0%, 97.5% and 99.9% with 20% variations in target thicknesses requires producing on average 1.2, 1.5 and 1.9 times the minimum daily activity requirement. The irradiation parameters that would be required to achieve these service rates are described. We believe the developed formalism will aid in the development of quality-control criteria required to ensure consistent supply of large quantities of high-radionuclidic-purity cyclotron-produced (99m)Tc.

A fast and simple dose-calibrator-based quality control test for the radionuclidic purity of cyclotron-produced (99m)Tc.

Cyclotron production of 99mTc through the (100)Mo(p,2n)99mTc reaction channel is actively being investigated as an alternative to reactor-based (99)Mo generation by nuclear fission of (235)U. Like most radioisotope production methods, cyclotron production of 99mTc will result in creation of unwanted impurities, including Tc and non-Tc isotopes. It is important to measure the amounts of these impurities for release of cyclotron-produced 99mTc (CPTc) for clinical use. Detection of radioactive impurities will rely on measurements of their gamma (γ) emissions. Gamma spectroscopy is not suitable for this purpose because the overwhelming presence of 99mTc and the count-rate limitations of γ spectroscopy systems preclude fast and accurate measurement of small amounts of impurities. In this article we describe a simple and fast method for measuring γ emission rates from radioactive impurities in CPTc. The proposed method is similar to that used to identify (99)Mo breakthrough in generator-produced 99mTc: one dose calibrator (DC) reading of a CPTc source placed in a lead shield is followed by a second reading of the same source in air. Our experimental and theoretical analysis show that the ratio of DC readings in lead to those in air are linearly related to γ emission rates from impurities per MBq of 99mTc over a large range of clinically-relevant production conditions. We show that estimates of the γ emission rates from Tc impurities per MBq of 99mTc can be used to estimate increases in radiation dose (relative to pure 99mTc) to patients injected with CPTc-based radiopharmaceuticals. This enables establishing dosimetry-based clinical-release criteria that can be tested using commercially-available dose calibrators. We show that our approach is highly sensitive to the presence of 93gTc, 93mTc, 94gTc, 94mTc, 95mTc, 95gTc, and 96gTc, in addition to a number of non-Tc impurities.

Intravascular ultrasonic analysis of plaque characteristics associated with coronary artery remodeling.

We sought to determine the patient and plaque characteristics associated with the different forms of arterial remodeling as seen by intravascular ultrasound (IVUS) before coronary intervention. Remodeling in response to plaque accumulation may occur in the form of compensatory enlargement and/or focal vessel contraction. Previous studies report variation in the frequency and form of arterial remodeling. We performed preintervention IVUS imaging on 169 patients. Vessels were categorized as exhibiting compensatory enlargement or focal contraction if the arterial area at the lesion was larger or smaller, respectively, than both proximal and distal reference arterial areas; otherwise the artery was considered not to have undergone significant remodeling. Calcification was assessed and noncalcified plaque density was measured by videodensitometry. Sixty-one of 169 patients (66 narrowings) (46 men and 15 women, age 56+/-11 years) had adequate reference segments. Remodeling occurred in 43 of 66 patients (65%): compensatory enlargement in 27 of 66 (41%) and focal contraction in 16 of 66 (24%). Lesions with focal contraction had significantly smaller arterial area (13.3+/-3.3 vs. 18.1+/-7.0 mm2, p = 0.02) and plaque area (9.5+/-2.8 vs 13.7+/-5.5 mm2, p<0.01). Cross-sectional stenosis was similar (71+/-9% vs. 75+/-10%, p = NS), as was plaque density (p = 0.20), eccentricity, and calcium. Patient age, gender, and lesion location were not related to the form of remodeling. Similarly, history of diabetes, hypercholesterolemia, or hypertension was not predictive. Smoking was the only risk factor associated with focal contraction (p<0.01). Thus, whereas compensatory enlargement appears to be the most common form of coronary artery remodeling, focal contraction occurs more often in smokers.

Local administration of L-703,081 using a composite polymeric stent reduces platelet deposition in canine coronary arteries.

We compared the effect on platelet deposition of the glycoprotein IIb/IIIa receptor antagonist L-703,081, administered locally via a drug delivery stent, with that of a standard metal stent in a canine coronary model. There was a significant reduction in platelet deposition using the L-703,081-impregnated stent compared with the bare metal stent. This study demonstrates an alternative route of delivery of GPIIb/IIIa antagonists with potential advantages over systemic administration.

Extent and distribution of in-stent intimal hyperplasia and edge effect in a non-radiation stent population.

Intimal hyperplasia within the body of the stent is the primary mechanism for in-stent restenosis; however, stent edge restenosis has been described after brachytherapy. Our current understanding about the magnitude of in vivo intimal hyperplasia and edge restenosis is limited to data obtained primarily from select, symptomatic patients requiring repeat angiography. The purpose of this study was to determine the extent and distribution of intimal hyperplasia both within the stent and along the stent edge in relatively nonselect, asymptomatic patients scheduled for 6-month intravascular ultrasound (IVUS) as part of a multicenter trial: Heparin Infusion Prior to Stenting. Planar IVUS measurements 1 mm apart were obtained throughout the stent and over a length of 10 mm proximal and distal to the stent at index and follow-up. Of the 179 patients enrolled, 140 returned for repeat angiography and IVUS at 6.4 +/- 1.9 months and had IVUS images adequate for analysis. Patients had 1.2 +/- 0.6 Palmaz-Schatz stents per vessel. There was a wide individual variation of intimal hyperplasia distribution within the stent and no mean predilection for any location. At 6 months, intimal hyperplasia occupied 29.3 +/- 16.2% of the stent volume on average. Lumen loss within 2 mm of the stent edge was due primarily to intimal proliferation. Beyond 2 mm, negative remodeling contributed more to lumen loss. Gender, age, vessel location, index plaque burden, hypercholesterolemia, diabetes, and tobacco did not predict luminal narrowing at the stent edges, but diabetes, unstable angina at presentation, and lesion length were predictive of in-stent intimal hyperplasia. In a non-radiation stent population, 29% of the stent volume is filled with intimal hyperplasia at 6 months. Lumen loss at the stent edge is due primarily to intimal proliferation.

Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.

1. Nicotinylalanine, an inhibitor of kynurenine metabolism, has been shown to elevate brain levels of endogenous kynurenic acid, an excitatory amino acid receptor antagonist. This study examined the potential of nicotinylalanine to influence excitotoxic damage to striatal NADPH diaphorase (NADPH-d) and gamma-aminobutyric acid (GABA)ergic neurones that are selectively lost in Huntington's disease. 2. A unilateral injection of the N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid, into the rat striatum produced an 88% depletion of NADPH-d neurones. Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content. 3. Nicotinylalanine (2.3, 3.2, 4.6, 6.4 nmol 5 microl(-1), i.c.v.) administered with L-kynurenine (450 mg kg(-1)), a precursor of kynurenic acid, and probenecid (200 mg kg(-1)), an inhibitor of organic acid transport, 3 h before the injection of quinolinic acid (15 nmol) produced a dose-related attenuation of the quinolinic acid-induced loss of NADPH-d neurones. Nicotinylalanine (5.6 nmol 5 microl(-1)) in combination with L-kynurenine and probenecid also attenuated quinolinic acid-induced reductions in striatal GABA content. 4. Nicotinylalanine (4.6 nmol, i.c.v.), L-kynurenine alone or L-kynurenine administered with probenecid did not attenuate quinolinic acid-induced depletion of striatal NADPH-d neurones. However, combined administration of kynurenine and probenecid did prevent quinolinic acid-induced reductions in ipsilateral striatal GABA content. 5. Injection of nicotinylalanine, at doses (4.6 nmol and 5.6 nmol i.c.v.) which attenuated quinolinic acid-induced striatal neurotoxicity, when combined with L-kynurenine and probenecid produced increases in both whole brain and striatal kynurenic acid levels. Administration of L-kynurenine and probenecid without nicotinylalanine also elevated kynurenic acid, but to a lesser extent. 6. The results of this study demonstrate that nicotinylalanine has the potential to attenuate quinolinic acid-induced striatal neurotoxicity. It is suggested that nicotinylalanine exerts its effect by increasing levels of endogenous kynurenic acid in the brain. The results of this study suggest that agents which influence levels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage to neurones in the CNS.