bluuebunny/crossref_metadata_2025 huggingface dataset:
Laboratory studies of the effect of sorbed oil on proton nuclear magnetic resonance
Authors: Bryar Traci R. , Knight Rosemary J.
Published: May 2003

Proton NMR (nuclear magnetic resonance) measurements were made of T1 and T2 relaxation times of water in saturated sands containing varying amounts of sorbed oil on the grain surfaces. The porosity, surface area, and grain density of the sands and the relaxation times of the extracted pore water were also determined experimentally. Sorption of oil changed the relaxation time of water in the saturated sands through changes in surface area and surface relaxivity, the parameter used to quantify the ability of the surface of the pore space to reduce NMR relaxation times. In some cases the addition of oil to the surfaces decreased the surface area, an observation that suggested the oil was coating the surface in a way to reduce surface roughness. When larger amounts of oil were added to the surface, surface area increased. The changes in surface relaxivity with the amount of sorbed oil were governed by the relaxivity of the clean, oil‐free surfaces. In the Wedron sand, with a surface relaxivity typical of naturally occurring sands, the relaxivity decreased with the addition of oil to the surface of the sand grains. In the A–A sand, a clean, pure quartz sand, the relaxivity increased from a very low value for the oil‐free sample to a higher value, interpreted to be that of the oil surface.
A finite‐difference time‐domain simulation tool for ground‐penetrating radar antennas
Authors: Lampe Bernhard , Holliger Klaus , Green Alan G.
Published: May 2003

The generation and recording of electromagnetic waves by typical ground‐penetrating radar (GPR) systems are complex phenomena. To investigate the characteristics of typical GPR antennas operating in diverse environments, we have developed a versatile and efficient simulation tool. It is based on a finite‐difference time‐domain (FDTD) approximation of Maxwell's equations that lets one simulate the radiation characteristics of a wide variety of typical surface GPR antenna systems. The accuracy of the algorithm is benchmarked and validated with respect to laboratory measurements for comparable antenna systems. Computed radiation patterns demonstrate that the illumination of the subsurface in the near‐ to intermediate‐field range varies significantly according to how the antenna is designed. Our models show the effects of varying the shapes of the antennas, adding shielding (metal box with and without absorbing material and with and without resistive loading), adding a receiver antenna, and changing the soil conditions. Given the flexibility of this modeling software, we anticipate that it will be helpful in designing GPR surveys and new GPR systems with arbitrary planar structures. It will also be useful in interpreting certain GPR data sets.
Merging airborne magnetic surveys into continental‐scale compilations
Authors: Minty Brian R. S. , Milligan Peter R. , Luyendyk Tony , Mackey Timothy
Published: May 2003

Regional compilations of airborne magnetic data are becoming more common as national databases grow. Grids of the magnetic survey data are joined together to form geological province‐scale or even continental‐scale compilations. The advantage of these compilations is that large tectonic features and geological provinces can be better mapped and interpreted.

We take a holistic approach to the joining of survey grids. The leveling of the grids into a regional compilation is treated as a single inverse problem. We use the weighted least‐squares method to find the best adjustment for each survey grid such that the data value differences in the grid overlap areas are minimized. The method spreads any inconsistencies between grids among all of the grid overlap areas and minimizes the introduction of long‐wavelength errors into the composite grid. This is an improvement on the conventional approach of joining grids sequentially.

A comparison of leveled data over Western Australia with diurnally‐corrected long aeromagnetic traverses shows long‐wavelength errors of about 200 nT over distances of more than 5000 km. This is an improvement on the sequential grid‐joining method, which gives errors of about 450 nT over the same distance. The application of the method to a smaller area covered by good quality surveys resulted in long‐wavelength errors of about 30 nT over a distance of 1200 km. This is within the estimated accuracy of the original survey measurements. The new method is also fast—what used to take many weeks of effort can now be achieved in a matter of hours.
Practical aspects and applications of 2D stereotomography
Authors: Billette Frederic , Bégat Soazig Le , Podvin Pascal , Lambaré Gilles
Published: May 2003

Stereotomography is a new velocity estimation method. This tomographic approach aims at retrieving subsurface velocities from prestack seismic data. In addition to traveltimes, the slope of locally coherent events are picked simultaneously in common offset, common source, common receiver, and common midpoint gathers. As the picking is realized on locally coherent events, they do not need to be interpreted in terms of reflection on given interfaces, but may represent diffractions or reflections from anywhere in the image. In the high‐frequency approximation, each one of these events corresponds to a ray trajectory in the subsurface. Stereotomography consists of picking and analyzing these events to update both the associated ray paths and velocity model. In this paper, we describe the implementation of two critical features needed to put stereotomography into practice: an automatic picking tool and a robust multiscale iterative inversion technique. Applications to 2D reflection seismic are presented on synthetic data and on a 2D line extracted from a 3D towed streamer survey shot in West Africa for TotalFinaElf. The examples demonstrate that the method requires only minor human intervention and rapidly converges to a geologically plausible velocity model in these two very different and complex velocity regimes. The quality of the velocity models is verified by prestack depth migration results.
Inversion of multicomponent, multiazimuth, walkaway VSP data for the stiffness tensor
Authors: Dewangan Pawan , Grechka Vladimir
Published: May 2003

Vertical seismic profiling (VSP), an established technique, can be used for estimating in‐situ anisotropy that might provide valuable information for characterization of reservoir lithology, fractures, and fluids. The P‐wave slowness components, conventionally measured in multiazimuth, walkaway VSP surveys, allow one to reconstruct some portion of the corresponding slowness surface. A major limitation of this technique is that the P‐wave slowness surface alone does not constrain a number of stiffness coefficients that may be crucial for inferring certain rock properties. Those stiffnesses can be obtained only by combining the measurements of P‐waves with those of S (or PS) modes.

Here, we extend the idea of Horne and Leaney, who proved the feasibility of joint inversion of the slowness and polarization vectors of P‐ and SV‐waves for parameters of transversely isotropic media with a vertical symmetry axis (VTI symmetry). We show that there is no need to assume a priori VTI symmetry or any other specific type of anisotropy. Given a sufficient polar and azimuthal coverage of the data, the polarizations and slownesses of P and two split shear (S1 and S2) waves are sufficient for estimating all 21 elastic stiffness coefficients cijthat characterize the most general triclinic anisotropy. The inverted stiffnesses themselves indicate whether or not the data can be described by a higher‐symmetry model.

We discuss three different scenarios of inverting noise‐contaminated data. First, we assume that the layers are horizontal and laterally homogeneous so that the horizontal slownesses measured at the surface are preserved at the receiver locations. This leads to a linear inversion scheme for the elastic stiffness tensor c. Second, if the S‐wave horizontal slowness at the receiver location is unknown, the elastic tensor c can be estimated in a nonlinear fashion simultaneously with obtaining the horizontal slowness components of S‐waves. The third scenario includes the nonlinear inversion for c using only the vertical slowness components and the polarization vectors of P‐ and S‐waves. We find the inversion to be stable and robust for the first and second scenarios. In contrast, errors in the estimated stiffnesses increase substantially when the horizontal slowness components of both P‐ and S‐waves are unknown. We apply our methodology to a multiazimuth, multicomponent VSP data set acquired in Vacuum field, New Mexico, and show that the medium at the receiver level can be approximated by an azimuthally rotated orthorhombic model.
Asymptotic pseudounitary stacking operators
Authors: Fomel Sergey
Published: May 2003

Stacking operators are widely used in seismic imaging and seismic data processing. Examples include Kirchhoff datuming, migration, offset continuation, dip moveout, and velocity transform. Two primary approaches exist for inverting such operators. The first approach is iterative least‐squares optimization, which involves the construction of the adjoint operator. The second approach is asymptotic inversion, where an approximate inverse operator is constructed in the high‐frequency asymptotics. Adjoint and asymptotic inverse operators share the same kinematic properties, but their amplitudes (weighting functions) are defined differently. This paper describes a theory for reconciling the two approaches. I introduce a pair of asymptotic pseudounitary operators, which possess both the property of being adjoint and the property of being asymptotically inverse. The weighting function of the asymptotic pseudounitary stacking operators is shown to be completely defined by the derivatives of the operator kinematics. I exemplify the general theory by considering several particular examples of stacking operators. Simple numerical experiments demonstrate a noticeable gain in efficiency when the asymptotic pseudounitary operators are applied for preconditioning iterative least‐squares optimization.
Parsimonious 2D prestack Kirchhoff depth migration
Authors: Hua Biaolong , McMechan George A.
Published: May 2003

The efficiency of prestack Kirchhoff depth migration is much improved by using ray parameter information measured from prestack common‐source and common‐receiver gathers. Ray tracing is performed only back along the emitted and emergent wave directions, and so is much reduced. The position of the intersection of the source and receiver rays is adjusted to satisfy the image time condition. The imaged amplitudes are spread along the local reflector surface only within the first Fresnel zone. There is no need to build traveltime tables before migration because the traveltime calculation is embedded into the migration. To further reduce the computation time, the input data are decimated by applying an amplitude threshold before the estimation of ray parameters, and only peak and trough points on each trace are searched for ray parameters.

Numerical results show that the proposed implementation is typically 50–80 times faster than traditional Kirchhoff migration for synthetic 2D prestack data. The migration speed improvement is obtained at the expense of some reduction in migration quality; the optimal compromise is implemented by the choice of migration parameters. The main uses of the algorithm will be to get a fast first look at the main structural features and for iterative migration velocity analysis.
Processes of taking a gap-filling test: comparison of skilled and less skilled EFL readers
Authors: Yamashita Junko
Published: May 2003

The present study investigates how skilled and less skilled readers answered a gap-filling (or rational deletion cloze) test in order to examine whether such tests can measure text-level processing ability. Twelve Japanese EFL students (six skilled and six less skilled readers) completed a gap-filling test while thinking aloud about their test-taking processes. Their verbal protocols were categorized according to the classification of cloze item types developed by Bachman (1985). Results showed that both skilled and less skilled readers used text-level information more frequently than other types of information. The skilled readers, however, used text-level information more frequently than the less skilled readers. Qualitative analysis of the protocols revealed further differences in the use of different types of information between the groups. Although there were several cases where the items were answered correctly with local grammatical clues and extra-textual background knowledge, overall, the gap-filling test generated text-level processing and differentiated well between skilled and less skilled readers. The present study, therefore, supports the claim that a gap-filling test can be used as a test to measure higher order processing ability.
Development of procedures to address health and safety issues in the administration of gene therapy within the clinical setting
Authors: Stoner Nicola S , Gibson Rachel N , Edwards Jeanette
Published: May 2003

Background. The Cancer Research UK Medical Oncology Unit is a clinical research unit with a 16- bed inpatient facility. Clinical research pharmacists are integral members of the multidisciplinary team. In the last three years, six gene therapy clinical trials have been undertaken, requiring containment level one facilities. The vectors used for gene transfer in these studies included inactivated retrovirus, adenovirus, herpes simplex virus and vaccinia.

Purpose. The aim of this paper is to highlight the procedures used throughout the clinical trial process, including storage, handling and disposal of the vectors, to minimize the health and safety risk to staff, patients and the environment.

Findings. Little researched evidence is available on the clinical implications of gene therapy, especially with regard to health and safety. Published literature and protocol guidelines were reviewed. Visits were made to other sites administering gene therapy, and national and international symposia were attended. Standard operating procedures for handling containment level one gene therapy vectors were produced to ensure safe practice. These are in accordance with current UK Health and Safety Executive guidelines.

Conclusions. The future treatment of the patient with cancer will conceivably involve genetic modification. There is, therefore, an urgent need for further research into the safety of these therapies to patients, clinicians, the general public and the environment. This is a new and exciting area for practice research.
External contamination of vials containing cytotoxic agents supplied by pharmaceutical manufacturers
Authors: Favier Bertrand , Gilles Laurence , Ardiet Claude , Latour Jean François
Published: May 2003

Objectives. The aim of this report was to study the external contamination of vials of 5-fluorour-acil, cyclophosphamide, ifosfamide, etoposide, doxorubicin and docetaxel. It also investigated the possible contamination of 5-fluorouracil outer packaging.

Methods. External contamination was measured on vials containing 5-fluorouracil, etoposide, cyclophosphamide, ifosfamide, doxorubicin and docetaxel. Samples from the outer wall of the vials were obtained by immersing and rotating the stoppered vials for 30 seconds in water for injections.

Results. All vials tested were contaminated with quantities varying from 0.5 ng to 2.4 g per vial, depending on the supplier. The outer packaging containing 25 vials of 5-fluorouracil was contaminated with 1.5 g, but no contamination was detected on the plastic packaging of etoposide.

Conclusion. These results demonstrate that the environment of operators may be contaminated, even in the absence of any handling error, and that contamination is present even before the cytotoxic reconstitution has begun. This source of exposure to cytotoxics may account for the contamination detected in the urine of operators. We demonstrate the necessity of protecting effectively all skin surfaces that are likely to come into contact with antineoplastic agents when unpacking the vials. Wearing long disposable gloves with adequate thickness (such as surgical gloves) is strongly recommended, from the very moment operators enter the preparation room. In general, the contamination of operators can only be controlled efficiently when all possible sources of contamination are considered, and suitable protection facilities are used (safety cabinet or isolator).
A review of imatinib mesilate in the treatment of patients with gastrointestinal stromal tumours and chronic myeloid leukaemia
Authors: Hole Alison , Blake Denise
Published: May 2003

Context. Imatinib mesylate (GlivecÒ, GleevecÒ, Novartis) has made a dramatic impact on the treatment available for both chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs). Both are rare diseases that have possibly been unfamiliar to many pharmacists until now.

Objective. To provide readers with a structured overview of CML and GISTs and the trial data available to support the role imatinib is playing in the treatment of these diseases.

Data sources. Published reviews and primary trial results were sourced via Medline to prepare the review. Articles published up to and including August 2002 were considered. Additionally, pertinent books were used to prepare the text and Novartis kindly supplied information currently only available on file at the company. As imatinib has only been available for a short time, all types and sizes of trials were considered for inclusion. The authors made the final decision as to the relevance and therefore subsequent inclusion of data.

Conclusions. Imatinib is a new molecularly targeted therapy for the treatment of CML and GISTs. It has provided an efficacious alternative therapy choice for physicians managing the care of patients suffering from these diseases. In the future there is the possibility that imatinib may demonstrate activity in other disease states characterized by the genetic changes targeted by imatinib. The results of randomized controlled trials in new and existing indications are awaited.
Implementation of a telephone callback service for ambulatory oncology patients
Authors: Dobish Roxanne B , Tulloch Karen J , Chambers Carole R
Published: May 2003

Introduction. A pilot project was established at the Cross Cancer Institute pharmacy to assess the feasibility of implementing a patient callback program to determine which patients would benefit from a callback and the impact a callback service would have on the workload of the pharmacy department.

Program description/development/implementation/evaluation. A pharmacy student conducted the pilot project over a 14-week time period. Four categories of patients were selected for inclusion in the pilot. The student approached patients at the time of medication pick-up to receive verbal permission to be included in the callback program. A standardized callback form was utilized to record medication information and any recommendations made. Data were collected on the numbers of patients in each category with questions or concerns as this was felt to be indicative of patients who would most benefit from a callback. The total time spent making the telephone calls was recorded. Over the eight-week period, 530.5 minutes were spent making the telephone calls with the average length of call being 3.27 minutes.

Discussion/conclusion. The student researcher proposed that three patient groups would benefit from receiving a callback: new patients or patients on new medications; elderly patients; and patients with specific disease-drug combinations. The project also provided an estimate of pharmacist time required to implement such a service and it was concluded that implementation could occur with minimal disruption to workflow.
Next-day chemotherapy scheduling: a multidisciplinary approach to solving workload issues in a tertiary oncology center
Authors: Dobish Roxanne
Published: May 2003

Introduction/background information. In 1998, increasing patient volumes and workloads related to ambulatory chemotherapy began to result in delays in the outpatient clinics, laboratory, pharmacy and the chemotherapy administration areas. The various departments that were being impacted met to review the situation and propose a solution.

Program description. The team proposed that a next-day chemotherapy schedule be implemented, whereby patients would have their laboratory and physician appointment on one day and their chemotherapy administered on the next day. Originally, this was turned down by senior management, however, a year later the same issues resurfaced and the next-day chemotherapy scheduling was once again proposed and approval received to implement.

Program implementation. A timetable was created and chemotherapy administration appointments were scheduled based on the available timeslots. The goal was to have the majority of patients scheduled for chemotherapy administration on the day following their appointment with the physician. Patients who would be exceptions to the next-day scheduling system were identified and education of staff and patients regarding the change was completed. Resistance from patients and staff was encountered and managed through continued education and reinforcement regarding the reasons for the change.

Pharmacy issues/evaluation. Pharmacy conducted a follow-up timing study and the results supported that the timetable change was successful in improving pharmacy’s ability to prepare the chemotherapy for the patient’s appointment time. Pharmacy operational issues had to be worked through, however, overall the change was found to be positive.

Conclusion. The implementation of a next-day chemotherapy administration schedule has resulted in improved efficiencies for pharmacy and nursing and a decrease in waiting times for patients to receive their chemotherapy.
Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: safety results from a phase I trial
Authors: Mohler Emile R , Rajagopalan Sanjay , Olin Jeffrey W , Trachtenberg Jeffrey D , Rasmussen Henrik , Pak Raphael , Crystal Ronald G
Published: May 2003

Critical limb ischemia (CLI) is typifi ed by rest pain and/or tissue necrosis secondary to advanced peripheral arterial disease (PAD) and is characterized by diminution in limb per-fusion at rest. We tested the safety of an angiogenic strategy with CI-1023 (AdGV VEGF121.10), a replication-defi cient adenovirus encoding human vascular endothelial growth factor isoform 121 in patients with CLI as part of a phase I trial. Fifteen subjects >35 years of age with CLI and angiographic disease involving the infra-inguinal vessels underwent intramuscular injection of CI-1023 (4 3 108 to 4 3 1010 particle units, n = 13) or placebo (n = 2). All of the patients tolerated the injection well and there were no serious complications related to the procedure. Transient edema was noted in one patient. A total of 79 adverse events were reported over the course of one year. One death (day 136) and one malignancy (day 332) occurred in the CI-1023 group. CI-1023 appears to be well tolerated and safe for single-dose administration in patients with critical limb ischemia due to PAD. Further studies are needed to determine the efficacy of this form of therapeutic angiogenesis.
Hypercoagulable state testing and malignancy screening following venous thromboembolic events
Authors: Deitcher Steven R , Gomes Marcelo PV
Published: May 2003

Mounting interest in hypercoagulability, increased availability of hypercoagulable state test ‘panels’ and enhanced ability to identify abnormalities in tested patients have prompted widespread testing. Testing for acquired and inherited hypercoagulable states uncovers an abnormality in over 50% of patients presenting with an initial venous thromboembolic event (VTE) but may have minimal actual impact on management in most of these patients. Such laboratory screening should be reserved for patients in whom the results of individual tests will signifi cantly impact the choice of anticoagulant agent, intensity of anticoagulant therapy, therapeutic monitoring, family screening, family planning, prognosis determination, and most of all duration of therapy. Testing ‘just to know’ is neither cost-effective nor clinically appropriate. The most important testing in patients following acute VTE may be ageand gender-specifi c cancer screening. Cancer screening following VTE seems most prudent in older individuals and in those with idiopathic VTE and no laboratory evidence for an inherited hypercoagulable state. Cancer screening should focus on identifi cation of treatable cancers and those where diagnosis in an early stage favorably impacts patient survival. Extensive searches for occult malignancy employing whole-body computed tomography and serum tumor markers may identify more cancers but without affecting patient outcome. We advocate that physicians should focus their attention more on VTE prophylaxis and proper treatment and less on costly and, at times, invasive testing of questionable value.
Leukocyte recruitment and expression of chemokines following different forms of vascular injury
Authors: Welt Frederick GP , Tso Colin , Edelman Elazer R. , Kjelsberg Michael A , Paolini John F , Seifert Philip , Rogers Campbell
Published: May 2003

Inflammation plays a central role in restenosis following coronary intervention. Recent human and animal data suggest important differences between the inflammatory responses to simple balloon angioplasty compared with stent implantation. To investigate the mechanisms of these differences, New Zealand white rabbits underwent bilateral iliac artery balloon denudation. Half received intravascular stents. Arteries were harvested at three, seven and 14 days for immunohistochemistry, and 4 hours, 8 hours and 14 days for chemokine mRNA analysis. Leukocyte content was quantifi ed utilizing immunohistochemistry (RPN357, monoclonal antibody (mAb) against rabbit neutrophil; RAM-11, mAb against rabbit macrophage). We analyzed the mRNA levels of the chemokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8) through semi-quantitative polymerase chain reaction. We demonstrated the spatial pattern of MCP-1 mRNA levels through in situ mRNA hybridization. In balloon-injured arteries, leukocyte recruitment was confi ned to early neutrophil infi ltration. IL-8 and MCP-1 mRNA levels peaked within hours and were undetectable at 14 days. In contrast, in stented arteries, early neutrophil recruitment was followed by prolonged macrophage accumulation. IL-8 and MCP-1 mRNA levels peaked within hours but were still detectable 14 days post injury. Conclusions: In contrast to balloon injury, stent-induced injury results in sustained chemokine expression and leukocyte recruitment. These data may have important implications for antirestenotic strategies.
Current concepts of mechanical cerebral protection during precutaneous carotid intervention
Authors: Macdonald Sumaira , Gaines Peter A
Published: May 2003

Major advances in the endovascular treatment of carotid artery stenosis are underway, with an emphasis on improving the safety profi le of the technique. This review highlights key areas in the concepts and design of available mechanical neuroprotection devices utilized during carotid stenting to minimize procedural cerebral embolization. The advantages and disadvantages of each system are explored and the available clinical experience is given. The size threshold of particulate material likely to be clinically relevant is examined and compared with pathological analysis of particles trapped by protection systems reported in the world literature. It is shown that the adverse neurological event rate in those protected is lower than that in historical studies of unprotected carotid stenting. Furthermore, the size range and numbers of particles trapped by protections systems are suffi cient to cause potential neurological injury if allowed passage to the brain. Further improvements in outcomes may require further refi nement of protection technology.
Acute symptomatic pulmonary embolism associated with long haul air travel to Sydney
Authors: Hertzberg Susan R , Roy Shiva , Hollis Greg , Brieger David , Chan Adam , Walsh Warren
Published: May 2003

The association between air travel and pulmonary embolism (PE) is recognized, but the absolute risk has not been quantifi ed. Due to its geographical isolation, more than 50% of international travelers arrive at Sydney airport after a flight of at least 9 hours. Patients who become acutely unwell upon disembarkation are taken to one of two hospitals. In this study we reviewed the presentations at these two hospitals. A retrospective analysis of all patients presenting to the emergency departments (ED) directly from Sydney International Airport with symptomatic PE over a three-year period was undertaken. Over 36 months, 17 patients were admitted from Sydney International Airport to the ED with acute PE. All patients had flown for at least 9 hours. Seven patients had risk factors for thromboembolic disease. During the period of our review 6.58 million passengers arrived in Sydney on flights of at least 9 hours in duration, representing an incidence of 2.57 per million. In conclusion, the incidence of acutely symptomatic PE in association with long distance air travel is low and the majority of patients survive following hospital presentation.
High circulating levels of cytokines (IL-6 and TNFa), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test
Authors: Signorelli Salvatore Santo , Mazzarino Maria Clorinda , Pino Luigi Di , Malaponte Grazia , Porto Carmela , Pennisi Giuseppe , Marchese Giuseppe , Costa Maria Pia , Digrandi Daniele , Celotta Gabriella , Virgilio Vittorio
Published: May 2003

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic inflammation. The aim of our study was to assess whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 6 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 6 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-I were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were signifi cantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001).

These results confi rm that white blood cell activation is characteristic of systemic atherosclerosis and that these inflammation markers increase in conditions of hemodynamic stress.
Vascular viewpoint
Authors: Prabhakaran Dorairaj , Anand Sonia S
Published: May 2003

Question: What are the effects of celecoxib, a selective COX-2 inhibitor on endothelial function?

Population: Fourteen male patients (46-77 years) with severe coronary artery disease and chronic stable angina who did not have a coronary revascularization procedure three months prior to randomization. All patients were on aspirin and statins.

Design and methods: Randomized double-blind, placebo-controlled crossover study. All patients received celecoxib 200 mg twice a day or matching placebo for two weeks. One patient discontinued study medication and was not included in the fi nal analysis. The primary outcome was endothelial function as assessed by flow-mediated and glycerol nitrate-induced vaso-dilation of the brachial artery after each treatment period using a high-resolution ultrasound device (10 MHz linear array transducer; WTS-2, Pie Medical, Indianapolis, IN, USA). Flow-mediated dilatation of the brachial artery was induced by the release of a wrist cuff inflated to suprasystolic blood pressure for 5 min. After release of the cuff pressure the arterial diameter was recorded every 15 s for 3 min. Secondary outcomes included oxidized LDL-cholesterol, high-sensitivity C-reactive protein (CRP) and prostaglandins (prostaglandin E2, 6-keto-prostag-landin-F1a-a stable metabolite of prostaglandin I2) and thromboxane B2 (an immediate and stable metabolite of thromboxane A2). Heart rate and blood pressure were also assessed.

Results: Flow-mediated vasodilation signifi cantly increased after celecoxib administration compared with placebo (3.3 6 0.4% versus 2.0 6 0.5%, p = 0.03). Glyceryl trinitrate (GTN)-induced vasodilatation remained unchanged. High-sensitivity CRP and oxidized LDL were signifi cantly lowered by celecoxib as compared with placebo (p = 0.02 and p = 0.03 respectively), and the prostaglandins, including thromboxane B2, were not signifi cantly altered. No changes in clinical parameters such as heart rate and blood pressure were observed.

Conclusion: Selective COX-2 inhibition improves endothelium-dependent vasodilation, reduces low-grade chronic inflammation and oxidative LDL in patients with coronary artery disease.
Cancer-Specific Mortality After Surgery or Radiation for Patients With Clinically Localized Prostate Cancer Managed During the Prostate-Specific Antigen Era
Authors: D’Amico Anthony V. , Moul Judd , Carroll Peter R. , Sun Leon , Lubeck Deborah , Chen Ming-Hui
Published: May 2003

Purpose: To determine whether pretreatment risk groups shown to predict time to prostate cancer–specific mortality (PCSM) after treatment at a single institution retained that ability in a multi-institutional setting.

Patients and Methods: From 1988 to 2002, 7,316 patients treated in the United States at 44 institutions with either surgery (n = 4,946) or radiation (n = 2,370) for clinical stage T1c-2, N0 or NX, M0 prostate cancer made up the study cohort. A Cox regression analysis was performed to determine the ability of pretreatment risk groups to predict time to PCSM after treatment. The relative risk (RR) of PCSM and 95% confidence intervals (CIs) were calculated for the intermediate- and high-risk groups relative to the low-risk group.

Results: Estimates of non-PCSM 8 years after prostate-specific antigen (PSA) failure were 4% v 15% (surgery versus radiation; Plog rank = .002) compared with 13% v 18% (surgery versus radiation; Plog rank = .35) for patients whose age at the time of PSA failure was less than 70 as compared with ≥ 70 years, respectively. The RR of PCSM after treatment for surgery-managed patients with high- or intermediate-risk disease was 14.2 (95% CI, 5.0 to 23.4; PCox < .0001) and 4.9 (95% CI, 1.7 to 8.1; PCox = .0037), respectively. These values were 14.3 (95% CI, 5.2 to 24.0; PCox < .0001) and 5.6 (95% CI, 2.0 to 9.3; PCox = .0012) for radiation-managed patients.

Conclusion: This study provided evidence to support the prediction of time to PCSM after surgery or radiation on the basis of pretreatment risk groups for patients with clinically localized prostate cancer managed during the PSA era.
Groups Potentially at Risk for Making Poorly Informed Decisions About Entry into Clinical Trials for Childhood Cancer
Authors: Simon Christian , Zyzanski Stephen J. , Eder Michelle , Raiz Pauline , Kodish Eric D. , Siminoff Laura A.
Published: May 2003

Purpose: Some patients may be at greater risk than others of enrolling on a randomized clinical trial (RCT) without fully understanding the implications. To investigate this possibility, this study poses the question, Do non–English-speaking Latino parents of children with leukemia show differences in their discussion of and understanding of an RCT when compared with English-speaking minority parents and with English-speaking majority (ie, white) parents? This research hypothesizes that factors such as social and educational status and the role of language interpreters may account for significant differences in the discussion and understanding of an RCT among the three groups.

Patients and Methods: A total of 108 parents are reported on, all of whom were observed, interviewed, and audiotaped during informed-consent discussions about participation in an RCT with their child’s oncologist. Comparisons among the groups were performed using χ2 tests and a one-way analysis of variance.

Results: Problems of consent-related communication and understanding were more frequent among parents of low social status who spoke little or no English than they were in the two other groups. Several factors may have contributed to this disparity, including language interpretation, social status, and prevailing cultural norms.

Conclusion: Some patients may be at greater risk than others of enrolling on an RCT without fully understanding the implications of their decision to do so. Numerous factors may contribute to this disparity, including language interpretation, social status, and prevailing cultural norms. Some specific strategies are suggested to help address this disparity.
Quality Assessment of Genetic Markers Used for Therapy Stratification
Authors: Ambros I.M. , Benard J. , Boavida M. , Bown N. , Caron H. , Combaret V. , Couturier J. , Darnfors C. , Delattre O. , Freeman-Edward J. , Gambini C. , Gross N. , Hattinger C.M. , Luegmayr A. , Lunec J. , Martinsson T. , Mazzocco K. , Navarro S. , Noguera R. , O’Neill S. , Pötschger U. , Rumpler S. , Speleman F. , Tonini G.P. , Valent A. , Van Roy N. , Amann G. , De Bernardi B. , Kogner P. , Ladenstein R. , Michon J. , Pearson A.D.J. , Ambros P.F.
Published: May 2003

Purpose: Therapy stratification based on genetic markers is becoming increasingly important, which makes commitment to the highest possible reliability of the involved markers mandatory. In neuroblastic tumors, amplification of the MYCN gene is an unequivocal marker that indicates aggressive tumor behavior and is consequently used for therapy stratification. To guarantee reliable and standardized quality of genetic features, a quality-assessment study was initiated by the European Neuroblastoma Quality Assessment (ENQUA; connected to International Society of Pediatric Oncology) Group.

Materials and Methods: One hundred thirty-seven coded specimens from 17 tumors were analyzed in 11 European national/regional reference laboratories using molecular techniques, in situ hybridization, and flow and image cytometry. Tumor samples with divergent results were re-evaluated.

Results: Three hundred fifty-two investigations were performed, which resulted in 23 divergent findings, 17 of which were judged as errors after re-evaluation. MYCN analyses determined by Southern blot and in situ hybridization led to 3.7% and 4% of errors, respectively. Tumor cell content was not indicated in 32% of the samples, and 11% of seemingly correct MYCN results were based on the investigation of normal cells (eg, Schwann cells). Thirty-eight investigations were considered nonassessable.

Conclusion: This study demonstrated the importance of revealing the difficulties and limitations for each technique and problems in interpreting results, which are crucial for therapeutic decisions. Moreover, it led to the formulation of guidelines that are applicable to all kinds of tumors and that contain the standardization of techniques, including the exact determination of the tumor cell content. Finally, the group has developed a common terminology for molecular-genetic results.
Cyclin D1 Overexpression in Bronchial Epithelia of Patients With Lung Cancer Is Associated With Smoking and Predicts Survival
Authors: Ratschiller D. , Heighway J. , Gugger M. , Kappeler A. , Pirnia F. , Schmid R.A. , Borner M.M. , Betticher D.C.
Published: May 2003

Purpose: Cyclin D1 is overexpressed in almost 60% of resectable non–small-cell lung cancer (NSCLC). In the absence of cyclin D1 gene amplification, overexpression is characterized by allelic imbalanced transcript levels.

Methods: The aims were to study cyclin D1 expression by immunohistochemistry and allelic balance of transcripts in tumor-free bronchial epithelia from patients with resectable NSCLC by using monoclonal antibodies (48 patients and 288 sites), microdissection/reverse transcriptase polymerase chain reaction/restriction fragment length polymorphism analyses (24 patients and 144 sites). Derived data were related to patient characteristics—in particular, smoking habits.

Results: In 167 (58%) of 288 sites, cyclin D1 was overexpressed, with cytoplasmic and nuclear sublocalization in 53% and 7% of all sites, respectively. Nuclear overexpression was more frequent in premalignant versus normal or hyperplastic epithelia (55% v 3%; P < .0001). Allele-specific expression imbalances were found in 69 (48%) of 144 sites; in particular, those in which cyclin D1 was overexpressed (P = .004). In 14 (58%) of 24 patients, balanced or imbalanced transcript ratios and degree of expression were consistent at all sites for the same patient, whereas in another 10 patients, transcript balances and cyclin D1 expression patterns varied across the sites. Nuclear cyclin D1 expression in at least one site (14 of 48 patients) was linked to heavy smoking (> 40 pack-years; P = .02) and shorter overall survival (P = .01).

Conclusion: Allele-specific, probably damage-driven, deregulation of the cyclin D1 gene may precede and perhaps facilitate the spread of preneoplastic clones across the bronchial epithelial surface in a significant number of patients. Cyclin D1 expression at multiple bronchial sites may identify a subgroup of heavy-smoking patients with poor outcome.
Phase III Study of Letrozole Versus Tamoxifen as First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group
Authors: Mouridsen Henning , Gershanovich Mikhail , Sun Yan , Pérez-Carrión Ramón , Boni Corrado , Monnier Alain , Apffelstaedt Justus , Smith Robert , Sleeboom Harm P. , Jaenicke Fritz , Pluzanska Anna , Dank Magdolna , Becquart Dominique , Bapsy Poonamalle P. , Salminen Eeva , Snyder Ray , Chaudri-Ross Hilary , Lang Raquel , Wyld Peter , Bhatnagar Ajay
Published: May 2003

Purpose: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer.

Patients and Methods: This multicenter phase III trial randomly assigned 916 patients with hormone receptor–positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician’s discretion. This report updates efficacy at a median follow-up of 32 months.

Results: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P < .0001), time to treatment failure (median, 9 v 5.7 months, respectively; P < .0001), overall objective response rate (32% v 21%, respectively; P = .0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy (“time to chemotherapy”) was significantly longer (P = .005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P = .001).

Conclusion: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.
Variations in the 5-Hydroxytryptamine Type 3B Receptor Gene as Predictors of the Efficacy of Antiemetic Treatment in Cancer Patients
Authors: Tremblay Pierre-Benoit , Kaiser Rolf , Sezer Orhan , Rösler Nadja , Schelenz Claudia , Possinger Kurt , Roots Ivar , Brockmöller Jürgen
Published: May 2003

Purpose: Serotonin (5-hydroxytryptamine type 3 [5-HT3]) receptor antagonists have substantially reduced but not eliminated nausea and vomiting in patients undergoing cancer chemotherapy. They act through specific binding to the 5-HT3A, 5-HT3B receptor complex. The 5-HT3B subunit seems to be most important for its functionality. We hypothesized that patients with genetic variations in the 5-HT3B receptor gene might respond differently to antiemetic treatment.

Patients and Methods: We included 242 cancer patients on their first day of chemotherapy. Nausea and vomiting were documented before and twice during the chemotherapy using standardized interviews and visual analog scales. We sequenced the entire 5-HT3B receptor gene, including the 5` flanking region and at least a 20–base pair intronic sequence of each intron-exon splice site of all patients.

Results: Approximately 30% of all patients suffered from nausea or vomiting. Sequencing of the 5-HT3B receptor gene revealed 13 polymorphisms: two of them were amino acid exchanges (Tyr129Ser, Ala223Thr) and two were deletion variants. In both observation periods, patients homozygous for the −100_−102delAAG deletion variant of the promotor region experienced vomiting more frequently than did all the other patients.

Conclusion: A more efficient antiemetic treatment with 5-HT3 receptor antagonists might be possible on a pharmacogenetic basis. However, only a small fraction of the therapeutic failure is explained by the −AAG deletion variant of the 5-HT3B receptor gene. Additional clinical and biochemical studies are needed to confirm the association.
Long-Term Follow-Up of a Prospective Study of Combined Modality Therapy for Stage I–II Indolent Non-Hodgkin’s Lymphoma
Authors: Seymour John F. , Pro Barbara , Fuller Lillian M. , Manning John T. , Hagemeister Fredrick B. , Romaguera Jorge , Rodriguez Maria A. , Ha Chul S. , Smith Terry L. , Ayala Ana , Hess Mark , Cox James D. , Cabanillas Fernando , McLaughlin Peter
Published: May 2003

Purpose: Standard therapy for patients with stage I–II indolent lymphoma has been involved-field radiation therapy (IF-XRT), which achieves 10-year disease-free survival in 40% to 50% of patients, with many of these patients cured. We investigated the potential for combined-modality therapy to increase the disease-free survival for such patients.

Patients and Methods: A total of 102 eligible patients with stage I–II low grade lymphoma (International Working Formulation criteria) were enrolled from 1984 to 1992. Treatment comprised 10 cycles of risk-adapted chemotherapy (cyclophosphamide, vincristine, prednisone, bleomycin [COP-Bleo], and with doxorubicin added for some [CHOP-Bleo]) and 30 to 40 Gy IF-XRT.

Results: The patients’ median age was 56 years (range, 28 to 77), with follicular histology in 83%, bulky disease (≥ 5 cm) in 24%, and stage II in 52%. There were no treatment-related deaths and 99% of patients attained complete remission. With a median follow-up of 10 years, the 10-year time to treatment failure and overall survival were 76% and 82%, respectively. For patients with follicular lymphoma, these figures were 72% and 80%, respectively. The only factor associated with treatment failure, for follicular lymphoma patients, was stage-modified International Prognostic Factors Index score (P = .02). None of 17 patients with diffuse small lymphocytic or mucosa-associated lymphoid tissue histology have relapsed. Elevated serum beta2-microglobulin was associated with shorter survival (P < .0001). The 10-year survival after relapse was 46%. There have been two cases of myelodysplasia and 12 other new malignancies, including four arising within radiation fields.

Conclusion: With prolonged follow-up, combined-modality therapy with risk-adapted COP-/CHOP-Bleo and IF radiation has attained higher rates of disease control and survival than previously reported with IF-XRT alone. This apparent improvement is being further explored in an ongoing randomized trial.